Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders

ABSTRACT

The present invention provides compounds useful, for example, for treating metabolic disorders in a subject. Such compounds have the general formula I:  
                 
 
where the definitions of the variables Q, L 1 ,  
                 
 
L 2 , M, X, L 3 , and A are provided herein. The present invention also provides compositions that include, and methods for using, the compounds in preparing medicaments and for treating metabolic disorders such as, for example, type II diabetes.

1. CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/717,432, filed on Sep. 14, 2005, which is hereby incorporated byreference in its entirety and for all purposes as if fully set forthherein.

2. FIELD OF THE INVENTION

The present invention relates to compounds capable of modulating theG-protein-coupled receptor GPR40, compositions comprising the compounds,and methods for their use for controlling insulin levels in vivo and forthe treatment of conditions such as type II diabetes, hypertension,ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia andrelated disorders associated with abnormally high or low plasmalipoprotein, triglyceride or glucose levels.

3. BACKGROUND OF THE INVENTION

The production of insulin is central to the regulation of carbohydrateand lipid metabolism. Insulin imbalances lead to conditions such as typeII diabetes mellitus, a serious metabolic disease that afflicts around5% of the population in Western Societies and over 150 million peopleworldwide. Insulin is secreted from pancreatic β cells in response toelevated plasma glucose which is augmented by the presence of fattyacids. The recent recognition of the function of the G-protein coupledreceptor GPR40 in modulating insulin secretion has provided insight intoregulation of carbohydrate and lipid metabolism in vertebrates, andfurther provided targets for the development of therapeutic agents fordisorders such as obesity, diabetes, cardiovascular disease anddyslipidemia.

GPR40 is a member of the gene superfamily of G-protein coupled receptors(“GPCRs”). GPCRs are membrane proteins characterized as having sevenputative transmembrane domains that respond to a variety of molecules byactivating intra-cellular signaling pathways critical to a diversity ofphysiological functions. GPR40 was first identified as an orphanreceptor (i.e., a receptor without a known ligand) from a human genomicDNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun.239: 543-547. GPR40 is highly expressed in pancreatic β cells andinsulin-secreting cell lines. GPR40 activation is linked to modulationof the G_(q) family of intra-cellular signaling proteins and concomitantinduction of elevated calcium levels. It has been recognized that fattyacids serve as ligands for GPR40, and that fatty acids regulate insulinsecretion through GPR40. Itoh et al. (2003) Nature 422:173-176; Briscoeet al. (2003) J. Biol. Chem. 278:11303-11311; Kotarsky et al. (2003)Biochem. Biophys. Res. Commun. 301: 406-410.

Various documents have disclosed compounds reportedly having activitywith respect to GPR40. For example, WO 2004/041266 and EP 1559422disclose compounds that purportedly act as GPR40 receptor functionregulators. WO 2004/106276 and EP 1 630 152 are directed to condensedring compounds that purportedly possess GPR40 receptor functionmodulating action. More recently, WO 2005/086661 and U.S. PatentPublication No. 2006/0004012 disclose compounds useful for modulatinginsulin levels in subjects and useful for treating type II diabetes.

Although a number of compounds have been disclosed that reportedlymodulate GPR40 activity, the prevalence of type II diabetes, obesity,hypertension, cardiovascular disease and dyslipidemia underscores theneed for new therapies to effectively treat or prevent these conditions.

4. SUMMARY OF THE INVENTION

Provided herein are compounds, pharmaceutical compositions and methodsuseful for treating or preventing a condition or disorder such as typeII diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema.

In one aspect, the compounds of the invention have the general formulaI:

where Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; L¹ is a bond, (C₁-C₄)alkylene,(C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b));

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring;L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂; M is anaromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene, or heteroaryl(C₁-C₄)alkylene; X is CR¹R^(1′),N(R^(1″)), O, or S(O)_(k); L³ is (C₁-C₅)alkylene or(C₂-C₅)heteroalkylene; A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂,—SO₂NH₂, —C(O)NHSO₂CH₃, —CHO, thiazolidinedionyl, hydroxyphenyl, orpyridyl; R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃) alkyl or(C₂-C₆)heteroalkyl; R^(b) is hydrogen, (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl; R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³; R^(1′) ishydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl; R² and R³ areindependently selected from hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl, or,optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached thatincludes from 0 to 2 additional heteroatoms selected from N, O, or S;and the subscript k is 0, 1 or 2.

In certain embodiments, the present invention provides a compound havingthe formula II:

where Q,

L² and R¹ are as defined above with respect to formula I, and each R⁴ isindependently selected from the group consisting of substituted(C₁-C₆)alkyl, —R′, ═O, —OR′, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl and heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; the subscript n is 0, 1 or 2; each R⁵ is independently selectedfrom the group consisting of (C₁-C₆)alkyl, halo(C₁-C₃)alkyl,hetero(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, and nitro; and thesubscript p is 0, 1, 2, 3 or 4. In some such embodiments, Q is selectedfrom hydrogen, aryl, or heteroaryl; L² is selected from O, or S(O)_(k);R¹ is selected from (C₂-C₈)alkynyl, aryl, heteroaryl, or —C(O)NR²R³; R²and R³ are independently selected from hydrogen or (C₁-C₄)alkyl; and R⁵is independently selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,cyano, or nitro. In some embodiments, R⁴ is independently selected from(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro.

In certain embodiments, the present invention provides a compound havingthe formula III:

where Q,

L², R¹, R⁴ and the subscripts n are as defined with respect to formulaII above.

In certain embodiments, the compound has the formula IV:

where Q, L², R¹, R⁴, and the subscript n are as defined above withrespect to formula II, and the subscript m is 1, 2, 3 or 4.

In certain embodiments, the present invention provides a compound havingthe formula V:

where Q, L², R¹, R⁴, and the subscript n are as defined above withrespect to formula II.

In some embodiments, the present invention provides a compound havingthe formula VI:

where Q, L², R¹, R⁴, and the subscript n are as defined above withrespect to formula II.

In some embodiments, the present invention provides a compound havingthe formula VII:

where Q, L², R¹, R⁴, and the subscript n are as defined above withrespect to formula II.

In some embodiments, the present invention provides a compound havingthe formula X or XI:

where Q, R⁴, and the subscript n are as defined with respect to formulaI or formula II above, and the subscript m is 1, 2, 3 or 4.

In another aspect, the present invention provides a compound having theformula (I):

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl. Incertain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)). In certain embodiments, L¹is a bond.

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring.In certain embodiments,

is a substituted cyclohexane ring or an unsubstituted cyclohexane ring.In certain embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring).

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)) or (C₂-C₄)alkenylene-N(R^(b))SO₂, wherethe subscript k is 0, 1 or 2. In certain embodiments, L² is O orS(O)_(k), where the subscript k is 0, 1 or 2. In certain embodiments, L²is —O—, —S— or —S(O)—, where Q is aryl or heteroaryl, and

is cyclohexyl. In certain embodiments, L¹ is a bond and L² is —O—, —S—or —S(O)—. In certain embodiments, L² is —O—, —S— or —S(O)—, where Q isaryl or heteroaryl, and

is cyclohexyl.

X is CR¹R^(1′).

L³ is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene, provided thatL³ is not a bond when L² is a bond. In some embodiments, L³ is a(C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene. In certain embodiments,L³ is (C₁-C₃)alkylene. In some embodiments, L³ is methylene. In certainembodiments, L³ is a methylene substituted with a monocyclic aryl ormonocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In certain embodiments,A is —CO₂H or a salt thereof. In some embodiments, A is —CO₂H or analkyl ester thereof. In some such embodiments, A is a C₁-C₆ alkyl estersuch as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl. In certain embodiments, R^(a) is (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

M is a benzene ring, and R¹ is combined with M to form a 5-, 6- or7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatomsselected from N, O and S. The following structures exemplify someembodiments where R¹ is combined with the adjacent benzene ring, i.e.,M, to form a benzo-fused cycloalkane ring:

where the dotted lines depict the sites of attachment to L² and L³offormula I. In certain embodiments, M is a benzene ring substituted inaddition to where it is bonded to R¹. In some embodiments, M is abenzene ring that is bonded to R¹ but is otherwise unsubstituted.

In some embodiments, R¹ is combined with the adjacent benzene ring toform a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1or 2 heteroatoms selected from N, O and S. The following structures ofM-X-L³-A exemplify some embodiments where R¹ is combined with theadjacent benzene ring to form a benzo-fused cycloalkane ring:

where the dotted lines depict the sites of attachment to L² of formulaI, and the wavy bonds indicate that a chiral carbon is present. Incertain such embodiments, the compound can be a stereoisomerically purecompound. In some embodiments, the compound can be a mixture ofstereoisomers. In some embodiments, M is a benzene ring substituted inaddition to where it is bonded to R¹. In other embodiments, M is abenzene ring that is bonded to R¹ but is otherwise unsubstituted.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl.

In some embodiments, R^(1′) is hydrogen or methyl.

In preferred embodiments, R^(1′) is hydrogen.

In some embodiments, the compound of formula I comprises astereomerically pure stereoisomer. In other embodiments, the compound offormula I

In another aspect, the present invention provides a compound having theformula (I):

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond.

represents an optionally substituted (C₅-C₈)cycloalkane ring.

In certain embodiments,

is a substituted cyclohexane ring, an unsubstituted cyclohexane ring, asubstituted cyclopentane ring, or an unsubstituted cyclopentane ring.

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)) or (C₂-C₄)alkenylene-N(R^(b))SO₂, wherethe subscript k is 0, 1 or 2.

In certain embodiments, L² is O or S(O)_(k), where the subscript k is 0,1 or 2.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl,and

is cyclohexyl.

In certain embodiments, L¹ is a bond and L² is —O—, —S— or —S(O)—.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl,and

is cyclohexyl.

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl.

In some embodiments, M is an aromatic ring or is a heteroaromatic ring.

In certain embodiments, M is a monocyclic aromatic, a monocyclicheteroaromatic ring, or a (C₅-C₈)cycloalkylene.

In some embodiments, M is an unsubstituted monocyclic aromatic ring oris an unsubstituted monocyclic heteroaromatic ring.

In certain embodiments, M is a substituted benzene ring.

In some embodiments, M is an unsubstituted benzene ring.

X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k), where the subscript k is 0,1, or 2.

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene, provided thatL³ is not a bond when L² is a bond. In some embodiments, L³ is a(C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene.

In certain embodiments, L³ is (C₁-C₃)alkylene.

In some embodiments, L³ is methylene.

In certain embodiments, L³ is a methylene substituted with a monocyclicaryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl.

In certain embodiments, A is —CO₂H or a salt thereof.

In some embodiments, A is —CO₂H or an alkyl ester thereof. In some suchembodiments, A is a C₁-C₆ alkyl ester such as a methyl, ethyl, propyl,butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl.

In certain embodiments, R^(a) is (C₁-C₆)alkyl or (C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

R¹ is cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³. In some embodiments, R¹ is cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³.

In certain embodiments, R^(a) is (C₂-C₈)alkynyl, aryl, heteroaryl, or—C(O)NR²R³.

In certain embodiments, R¹ is a (C₂-C₈)alkynyl or a heteroaryl. In somesuch embodiments, R¹ is a (C₃-C₈)alkynyl. In other such embodiments, R¹is a heteroaryl.

In certain embodiments, R¹ is selected from the group consisting ofprop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl,thiazolyl, thiophenyl, triazolyl, and —C(O)NR²R³.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl.

In some embodiments, R^(1′) is hydrogen or methyl.

In some embodiments, R^(1′) is hydrogen.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl or—C(O)NR²R³, and R^(1′) is hydrogen.

R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl.

Optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached andincluding from 0 to 2 additional heteroatoms selected from N, O, or S.The ring formed by combining R² and R³ may be a saturated, unsaturated,or aromatic ring.

In some embodiments, the compound of formula I comprises astereomerically pure stereoisomer. In other embodiments, the compound offormula I comprises a mixture of stereoisomers.

In certain embodiments, L¹ is a bond, Q is H or aryl,

represents an optionally substituted cylopentane or cyclohexane ring, L²is O, oxymethylene, or oxyethylene, M is benzene and X is para to L², Xis CR¹R^(1′), R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³, R^(1′) isH, L³ is methylene, and A is CO₂H or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof. In some such embodiments, thecompound is a pharmaceutically acceptable salt or solvate thereof. Inother such embodiments, the compound is a prodrug which is, in someembodiments, an ester such as a (C₁-C₆)alkyl ester such as a methyl,ethyl, propyl, butyl, pentyl, or hexyl ester.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I.

In certain embodiments, the compound of the present invention is acompound of formula II or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, where Q is selected from hydrogen,aryl, or heteroaryl;

represents an optionally substituted cycloalkane ring; L² is selectedfrom O or S(O)_(k); R¹ is selected from (C₂-C₈)alkynyl, aryl,heteroaryl, or —C(O)NR²R³; optionally, R¹ is combined with the adjacentbenzene ring to form a 5-, 6- or 7-membered benzo-fused cycloalkane ringcontaining 0, 1 or 2 heteroatoms selected from N, O and S; R² and R³ areindependently selected from hydrogen or (C₁-C₄)alkyl; R⁴ isindependently selected from the group consisting of substituted(C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups; R⁵ is independently selected from the group consisting of(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, and nitro; the subscript kis 0, 1 or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, or 14; and the subscript p is 0, 1, 2, 3 or 4. In some suchembodiments, R⁴ is independently selected from (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or and nitro.

The compounds of the invention include pharmaceutically acceptablesalts, solvates, stereoisomers, or prodrugs thereof. In someembodiments, the compounds are pharmaceutically acceptable salts. Inother embodiments, the compounds are prodrugs such as esters of acarboxylic acid.

In another aspect, the invention provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier, diluent, or excipient,and a compound of formula I-XI.

In another aspect, the invention provides methods for treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, hypertension,cancer, and edema. Such methods include administering to a subject inneed thereof, a therapeutically effective amount of a compound offormula I-XI. In some such embodiments, the disease or condition is typeII diabetes. In some embodiments, a compound of formula I-XI isadministered with combination with a second therapeutic agent. In somesuch embodiments, the second therapeutic agent is metformin or is athiazolidinedione. The second therapeutic agent may be administeredbefore, during, or after administration of the compound of formula I-XI.

In another aspect, the invention provides methods for treating orpreventing a disease or condition responsive to the modulation of GPR40.Such methods include administering to a subject in need thereof, atherapeutically effective amount of a compound of formula I-XI.

In another aspect, the invention provides methods for treating orpreventing a disease or condition mediated, regulated, or influenced bypancreatic β cells. Such methods include administering to a subject inneed thereof, a therapeutically effective amount of a compound offormula I-XI.

In another aspect, the invention provides methods for modulating GPR40function in a cell. Such methods include contacting a cell with acompound of formula I-XI.

In another aspect, the invention provides methods for modulating GPR40function. Such methods include contacting GPR40 with a compound offormula I-XI.

In another aspect, the invention provides methods for modulatingcirculating insulin concentration in a subject. Such methods includeadministering a compound of formula I-XI to the subject. In some suchembodiments, the circulating insulin concentration is increased in thesubject after administration whereas in other such embodiments, thecirculating insulin concentration is decreased in the subject afteradministration.

In another aspect, the invention provides the use of a compound offormula I-XI for treating a disease or condition or for preparing amedicament for treating a disease or condition where the disease orcondition is selected from the group consisting of type II diabetes,obesity, hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.In some such embodiments, the disease or condition is type II diabetes.The compounds of the invention may also be used to prepare medicamentsthat include a second therapeutic agent such as metformin or athiazolidinedione.

In another aspect, the invention provides the use of a compound offormula I-XI for modulating GPR40 or for use in the preparation of amedicament for modulating GPR40.

In another aspect, the invention provides a therapeutic composition thatincludes a compound of formula I-XI and a second therapeutic agent suchas those described herein, for example, metformin or athiazolidinedione, as a combined preparation for simultaneous, separate,or sequential use in the treatment of a disease or condition mediated byGPR40. In some such embodiments, the disease or condition is type IIdiabetes. In some embodiments, the compound of formula I-XI and thesecond therapeutic agent are provided as a single composition, whereasin other embodiments they are provided separately as parts of a kit.

In one aspect, the invention provides a method of synthesizing acompound of formula XXIV.

The method includes: reacting a compound of formula XXII with a compoundof formula XXIII to produce the compound of formula XXIV, wherein thecompounds of formula XXII and XXIII have the following structures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, orC(O)NR²R³; R² and R³ are independently selected from hydrogen, aryl,heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl; or optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S; R⁴ is independently selected from substituted (C₁-C₆)alkyl,—R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, or —NO₂, whereinR′, R″ and R′″ are each independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ isindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro; p is 0, 1, 2, 3, or 4; m is 1,2, 3, or 4; n is 0, 1, or 2; Y is selected from substituted(C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroup; W is a leaving group; and further wherein, the compounds offormula XXII and XXIV can be a mixture of compounds having the R and Sstereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.

In some embodiments, W is selected from OH or a halogen. In some suchembodiments, W is OH and a phosphine selected from a trialkylphosphine,a dialkylarylphosphine, an alkyldiarylphosphine, or a triarylphosphineand an azodicarboxylate are used to react the compound of formula XXIIwith the compound of formula XXIII. In other such embodiments, W is ahalogen selected from Br or Cl, and a base is used to react the compoundof formula XXII with the compound of formula XXIII. In some embodiments,W is selected from OH, halogen, OTs, OMs, or OTf, where Ts isp-toluenesulfonyl, Ms is methanesulfonryl, and Tf istrifluoromethanesulfonryl.

In some embodiments, Alk is selected from methyl or ethyl.

In some embodiments, m is 1 or 2.

In some embodiments, n is 0.

In some embodiments, p is 0.

In some embodiments, Y is a halogen, and the method further comprisesreacting the compound of formula XXIV with a boronic acid compound. Insome such embodiments, the boronic acid compound has the formulaaryl-B(OH)₂ or alkyl-B(OH)₂.

In some embodiments, the method further includes removing the Alk groupof the compound of formula XXIV to form a compound of formula XXV or asalt thereof, and the compound of formula XXV has the followingstructure:

wherein Y, R⁴, n, m, R⁵, p, and R¹ have the definitions provided withrespect to the compounds of any of the embodiments of formula XXII,XXIII, and XXIV. In some such embodiments, the compound of formula XXIVis reacted in the presence of a hydroxide base to produce the compoundof formula XXV. In some such embodiments, the hydroxide base is selectedfrom LiOH, NaOH, KOH, or Ca(OH)₂.

Other objects, features and advantages of the invention will becomeapparent to those skilled in the art from the following description andclaims.

5. DETAILED DESCRIPTION OF THE INVENTION 5.1 Abbreviations andDefinitions

The terms “treat”, “treating” and “treatment”, as used herein, are meantto include alleviating or abrogating a condition or disease and/or itsattendant symptoms. The terms “prevent”, “preventing” and “prevention”,as used herein, refer to a method of delaying or precluding the onset ofa condition or disease and/or its attendant symptoms, barring a subjectfrom acquiring a condition or disease, or reducing a subject's risk ofacquiring a condition or disease.

The term “therapeutically effective amount” refers to that amount of thecompound that will elicit the biological or medical response of atissue, system, or subject that is being sought. The term“therapeutically effective amount” includes that amount of a compoundthat, when administered, is sufficient to prevent development of, oralleviate to some extent, one or more of the symptoms of the conditionor disorder being treated in a subject. The therapeutically effectiveamount in a subject will vary depending on the compound, the disease andits severity, and the age, weight, etc., of the subject to be treated.

The term “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function or activity of GPR40either directly or indirectly. Inhibitors are compounds that, forexample, bind to, partially or totally block stimulation, decrease,prevent, delay activation, inactivate, desensitize, or down regulatesignal transduction, such as, for instance, antagonists. Activators arecompounds that, for example, bind to, stimulate, increase, activate,facilitate, enhance activation, sensitize or up regulate signaltransduction, such as agonists for instance. Modulation may occur invitro or in vivo.

As used herein, the phrases “GPR40-mediated condition or disorder”,“disease or condition mediated by GPR40”, and the like refer to acondition or disorder characterized by inappropriate, for example, lessthan or greater than normal, GPR40 activity. A GPR40-mediated conditionor disorder may be completely or partially mediated by inappropriateGPR40 activity. However, a GPR40-mediated condition or disorder is onein which modulation of GPR40 results in some effect on the underlyingcondition or disease (e.g., a GPR40 modulator results in someimprovement in patient well-being in at least some patients). ExemplaryGPR40-mediated conditions and disorders include cancer and metabolicdisorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis,hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X andrelated disorders, e.g., cardiovascular disease, atherosclerosis, kidneydisease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, and edema.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which is fully saturated,having the number of carbon atoms designated (e.g., C₁-C₁₀ means one toten carbons). Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl,(cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, and homologs andisomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike.

The term “alkenyl”, by itself or as part of another substituent, means astraight or branched chain, or cyclic hydrocarbon radical, orcombination thereof, which may be mono- or polyunsaturated, having thenumber of carbon atoms designated (i.e., C₂-C₈ means two to eightcarbons) and one or more double bonds. Examples of alkenyl groupsinclude vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), and higher homologs and isomersthereof.

The term “alkynyl”, by itself or as part of another substituent, means astraight or branched chain hydrocarbon radical, or combination thereof,which may be mono- or polyunsaturated, having the number of carbon atomsdesignated (i.e., C₂-C₈ means two to eight carbons) and one or moretriple bonds. Examples of alkynyl groups include ethynyl, 1- and3-propynyl, 3-butynyl, and higher homologs and isomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from alkyl, as exemplified by —CH₂CH₂CH₂CH₂—.Typically, an alkyl (or alkylene) group will have from 1 to 24 carbonatoms, with those groups having 12 or fewer carbon atoms being preferredin the present invention. A “lower alkyl” or “lower alkylene” is ashorter chain alkyl or alkylene group, generally having eight or fewercarbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. Similarly, the term dialkylaminorefers to an amino group having two attached alkyl groups. The alkylgroups of a dialkylamino may be the same or different.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting ofcarbon atoms and from one to three heteroatoms selected from the groupconsisting of O, N, and S, and wherein the nitrogen and sulfur atoms mayoptionally be oxidized, and the nitrogen heteroatom may optionally bequaternized. The heteroatom(s) O, N, and S may be placed at any positionof the heteroalkyl group. Examples include —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, and —CH₂—CH═N—OCH₃. Up to two heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃. When a prefix such as(C₂-C₈) is used to refer to a heteroalkyl group, the number of carbons(2 to 8, in this example) is meant to include the heteroatoms as well.For example, a C₂-heteroalkyl group is meant to include, for example,—CH₂OH (one carbon atom and one heteroatom replacing a carbon atom) and—CH₂SH.

To further illustrate the definition of a heteroalkyl group, where theheteroatom is oxygen, a heteroalkyl group is a, oxyalkyl group. Forinstance, (C₂-C₅)oxyalkyl is meant to include, for example —CH₂—O—CH₃ (aC₃-oxyalkyl group with two carbon atoms and one oxygen replacing acarbon atom), —CH₂CH₂CH₂CH₂OH, and the like.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical derived from heteroalkyl, as exemplified by—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Thus, the terms“cycloalkyl” and “heterocycloalkyl” are meant to be included in theterms “alkyl” and “heteroalkyl,” respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl,3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkylinclude 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The term “cycloalkylene” and “heterocycloalkylene,” by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkylene” and “heteroalkylene,” respectively. Thus, theterms “cycloalkylene” and “heterocycloalkylene” are meant to be includedin the terms “alkylene” and “heteroalkylene,” respectively.Additionally, for heterocycloalkylene, one or more heteroatoms canoccupy positions at which the heterocycle is attached to the remainderof the molecule. Typically, a cycloalkylene or heterocycloalkylene willhave from 3 to 9 atoms forming the ring, more typically, 4 to 7 atomsforming the ring, and even more typically, 5 or 6 atoms will form thecycloalkylene or hetercycloalkylene ring.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl”, aremeant to include alkyl substituted with halogen atoms which can be thesame or different, in a number ranging from one to (2m′+1), where m′ isthe total number of carbon atoms in the alkyl group. For example, theterm “halo(C₁-C₄)alkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus,the term “haloalkyl” includes monohaloalkyl (alkyl substituted with onehalogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms ina number ranging from two to (2m′+1) halogen atoms). The term“perhaloalkyl? means, unless otherwise stated, alkyl substituted with(2m′+1) halogen atoms, where m′ is the total number of carbon atoms inthe alkyl group. For example, the term “perhalo(C₁-C₄)alkyl”, is meantto include trifluoromethyl, pentachloroethyl,1,1,1-trifluoro-2-bromo-2-chloroethyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon substituent which can be a single ringor multiple rings (up to three rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from the group consistingof N, O and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of aryl and heteroarylgroups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,dibenzofuryl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl,5-benzoxazolyl, benzo[c][1,2,5]oxadiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1H-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl,γ-carbolinyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl,5-quinoxalinyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl,6-quinolyl, 7-quinolyl, and 8-quinolyl.

Preferably, the term “aryl” refers to a phenyl or naphthyl group whichis unsubstituted or substituted. Preferably, the term “heteroaryl”refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl,isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl,triazolyl, tetrazolyl, quinoxalinyl, or quinolyl group which isunsubstituted or substituted.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) is meant to include both substituted and unsubstitutedforms of the indicated radical, unless otherwise indicated. Preferredsubstituents for each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (as well as thosegroups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl,alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl andheterocycloalkenyl) can be a variety of groups selected from: —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR′R′″,—NR″CO₂′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, and —NO₂, in a number rangingfrom zero to three, with those groups having zero, one or twosubstituents being particularly preferred. R′, R″ and R′″ eachindependently refer to hydrogen, unsubstituted (C₁-C₈)alkyl andheteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6- or 7-membered ring. For example, —NR′R″is meant to include 1-pyrrolidinyl and 4-morpholinyl.

Typically, an alkyl or heteroalkyl group will have from zero to threesubstituents, with those groups having two or fewer substituents beingpreferred in the present invention. More preferably, an alkyl orheteroalkyl radical will be unsubstituted or monosubstituted. Mostpreferably, an alkyl or heteroalkyl radical will be unsubstituted. Fromthe above discussion of substituents, one of skill in the art willunderstand that the term “alkyl” is meant to include groups such astrihaloalkyl (e.g., —CF₃ and —CH₂CF₃).

Preferred substituents for the alkyl and heteroalkyl radicals areselected from: —OR′, ═O, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, and —NO₂, where R′ and R″ areas defined above. Further preferred substituents are selected from:—OR′, ═O, —NR′R″, halogen, —OC(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR″CO₂R′, —NR′—SO₂NR″R′″, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN,and —NO₂.

Similarly, substituents for the aryl and heteroaryl groups are variedand are selected from: -halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN,—NO₂, —CO₂R′, —CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′,—NR′—C(O)NR″R′″, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —N₃, —CH(Ph)₂, perfluoro(C₁-C₄)alkoxy, andperfluoro(C₁-C₄)alkyl, in a number ranging from zero to the total numberof open valences on the aromatic ring system; and where R′, R″ and R′″are independently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl,and (unsubstituted aryl)oxy-(C₁-C₄)alkyl.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CH₂)_(q)—U—, wherein T and U are independently —NH—, —O—,—CH₂—, or a single bond, and q is an integer of from 0 to 2.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CH₂—, —O—,—NH—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or a single bond, and r is aninteger of from 1 to 3. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CH₂)_(s)—X—(CH₂)_(t)—, where s and t are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R′ in —NR′— and —S(O)₂NR′— is selected from hydrogen orunsubstituted (C₁-C₆)alkyl. Otherwise, R′ is as defined above.

As used herein, the term “benzo-fused cycloalkane ring” is meant toinclude bicyclic structures in which benzene is fused with a cycloalkane(or cycloheteroalkane). To illustrate, in some embodiments, “benzo-fusedcycloalkane ring” includes the following structures:

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), and sulfur (S).

The term “pharmaceutically acceptable salt” is meant to include a saltof the active compound which is prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on the compounddescribed herein. When a compound of the invention contains relativelyacidic functionalities, a base addition salt can be obtained bycontacting the neutral form of such compound with a sufficient amount ofthe desired base, either neat or in a suitable inert solvent. Examplesof pharmaceutically acceptable base addition salts include sodium,potassium, calcium, ammonium, organic amino, or magnesium salt, or asimilar salt. When a compound of the invention contains relatively basicfunctionalities, an acid addition salt can be obtained by contacting theneutral form of such compound with a sufficient amount of the desiredacid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic,phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginine and the like, and salts of organic acids likeglucuronic or galacturonic acids and the like (see, for example, Bergeet al. (1977) J. Pharm. Sci. 66:1-19). Certain specific compounds of theinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the invention.

In addition to salt forms, the invention provides compounds which are ina prodrug form. Prodrugs of the compounds described herein are thosecompounds that readily undergo chemical changes under physiologicalconditions to provide the compounds of the invention. Additionally,prodrugs can be converted to the compounds of the invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the invention when placed ina transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent drug is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. A wide variety of prodrug derivatives are known inthe art, such as those that rely on hydrolytic cleavage or oxidativeactivation of the prodrug. An example, without limitation, of a prodrugwould be a compound of the invention which is administered as an ester(the “prodrug”), but then is metabolically hydrolyzed to the carboxylicacid, the active entity. Additional examples include peptidylderivatives of a compound.

As used herein, “solvate” refers to a compound of the present inventionor a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of solvent bound by non-covalentintermolecular forces. Where the solvent is water, the solvate is ahydrate.

Certain compounds of the invention may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the invention and are intended to be within thescope of the invention.

As known by those skilled in the art, certain compounds of the inventionmay exist in one or more tautomeric forms. Because one chemicalstructure may only be used to represent one tautomeric form, it will beunderstood that referral to a compound of a given structural formulaincludes tautomers of the structure represented by the structuralformula.

Certain compounds of the invention possess asymmetric carbon atoms(optical centers) or double bonds; the racemates, enantiomers,diastereomers, geometric isomers and individual isomers are all intendedto be encompassed within the scope of the invention.

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a compound that issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure compound having one chiral center will besubstantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. If the stereochemistry of astructure or a portion of a structure is not indicated with, forexample, bold or dashed lines, the structure or portion of the structureis to be interpreted as encompassing all stereoisomers of it. A bonddrawn with a wavy line indicates that both stereoisomers areencompassed.

Various compounds of the invention contain one or more chiral centers,and can exist as racemic mixtures of enantiomers, mixtures ofdiastereomers or enantiomerically or optically pure compounds. Thisinvention encompasses the use of stereomerically pure forms of suchcompounds, as well as the use of mixtures of those forms. For example,mixtures comprising equal or unequal amounts of the enantiomers of aparticular compound of the invention may be used in methods andcompositions of the invention. These isomers may be asymmetricallysynthesized or resolved using standard techniques such as chiral columnsor chiral resolving agents. See, e.g., Jacques, J., et al., Enantiomers,Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen,S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistryof Carbon Compounds (McGraw-Hill, N.Y., 1962); and Wilen, S. H., Tablesof Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed.,Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

The compounds of the invention may also contain unnatural proportions ofatomic isotopes at one or more of the atoms that constitute suchcompounds. For example, the compounds may be radiolabeled withradioactive isotopes, such as for example tritium (³H), iodine-125(¹²⁵I) or carbon-14 (¹⁴C). Radiolabeled compounds are useful astherapeutic or prophylactic agents, research reagents, e.g., GPR40 assayreagents, and diagnostic agents, e.g., in vivo imaging agents. Allisotopic variations of the compounds of the invention, whetherradioactive or not, are intended to be encompassed within the scope ofthe invention.

5.2 EMBODIMENTS OF THE INVENTION

In one aspect, a class of compounds that modulates GPR40 is describedherein. Depending on the biological environment (e.g., cell type,pathological condition of the subject, etc.), these compounds canmodulate, e.g., activate or inhibit, the actions of GPR40. By modulatingGPR40, the compounds find use as therapeutic agents capable ofregulating insulin levels in a subject. The compounds find use astherapeutic agents for modulating diseases and conditions responsive tomodulation of GPR40 and/or mediated by GPR40 and/or mediated bypancreatic β cells. As noted above, examples of such diseases andconditions include diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, cancer, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis,hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, nephropathy, thrombotic disorders,diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia andedema. Additionally, the compounds are useful for the treatment and/orprevention of complications of these diseases and disorders (e.g., typeII diabetes, sexual dysfunction, dyspepsia and so forth).

While the compounds of the invention are believed to exert their effectsby interacting with GPR40, the mechanism of action by which thecompounds act is not a limiting embodiment of the invention.

Compounds contemplated by the invention include, but are not limited to,the exemplary compounds provided herein.

5.2.1 Compounds

In one aspect, the present invention provides a compound having theformula (I):

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond.

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring.

In certain embodiments,

is a substituted cyclohexane ring or an unsubstituted cyclohexane ring.

In certain embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring.

In some embodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring, the benzo-fused cycloalkanering comprises 0-3 heteroatom ring members selected from O, N, or S. Insome such embodiments, the benzo-fused (C₅-C₈)cycloalkane ring comprises1 or 2 heteroatom ring members selected from O or N, and in someembodiments 1 heteroatom ring member, selected from O or N. In someembodiments, the benzo-fused (C₅-C8)cycloalkane comprises 0 heteroatomring atoms, does not include any heteroatoms in the ring, such that eachof the ring members of the benzo-fused (C₅-C₈)cycloalkane is a carbonatom. In some embodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring).

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C4)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,

(C₂-C₄)alkenylene-SO₂N(R^(b)) or (C₂-C₄)alkenylene-N(R^(b))SO₂, wherethe subscript k is 0, 1 or 2.

In certain embodiments, L² is O or S(O)_(k), where the subscript k is 0,1 or 2.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl, and is cyclohexyl.

In certain embodiments, L¹ is a bond and L² is —O—, —S— or —S(O)—.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl, and is cyclohexyl.

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl.

In some embodiments, M is an aromatic ring or is a heteroaromatic ring.

In certain embodiments, M is a monocyclic aromatic, a monocyclicheteroaromatic ring, or a (C₅-C₈)cycloalkylene.

In some embodiments, M is an unsubstituted monocyclic aromatic ring oris an unsubstituted monocyclic heteroaromatic ring.

In certain embodiments, M is a substituted benzene ring.

In some embodiments, M is an unsubstituted benzene ring.

X is CR¹R^(′), N(R′″), O, or S(O)_(k), where the subscript k is 0, 1, or2.

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene, provided thatL³ is not a bond when L² is a bond. In some embodiments, L³ is a(C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene.

In certain embodiments, L³ is (C₁-C₃)alkylene.

In some embodiments, L³ is methylene.

In certain embodiments, L³ is a methylene substituted with a monocyclicaryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl.

In certain embodiments, A is —CO₂H or a salt thereof. In some suchembodiments, the salt is a sodium, potassium, or calcium salt.

In some embodiments, A is —CO₂H or an alkyl ester thereof. In some suchembodiments, A is a C₁-C₆ alkyl ester such as a methyl, ethyl, propyl,butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl.

In certain embodiments, R^(a) is (C₁-C₆)alkyl or (C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

R¹ is cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³. In some embodiments, R¹ is cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl, or—C(O)NR²R³.

In certain embodiments, R¹ is a (C₂-C₈)alkynyl or a heteroaryl. In somesuch embodiments, R¹ is a (C₃-C₈)alkynyl. In other such embodiments, R¹is a heteroaryl.

In certain embodiments, R¹ is selected from the group consisting ofprop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl,thiazolyl, thiophenyl, triazolyl, and —C(O)NR²R³.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl.

In some embodiments, R^(1′) is hydrogen or methyl.

In preferred embodiments, R^(1′) is hydrogen.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl or—C(O)NR²R³, and R^(1′) is hydrogen.

R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C8)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl.

Optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached andincluding from 0 to 2 additional heteroatoms selected from N, O, or S.The ring formed by combining R² and R³ may be a saturated, unsaturated,or aromatic ring.

In some embodiments, the compound of formula I comprises astereomerically pure stereoisomer. In other embodiments, the compound offormula I comprises a mixture of stereoisomers.

In certain embodiments, L¹ is a bond, Q is H or aryl,

represents a substituted benzo-fused (C₅-C₈)cycloalkane ring or anunsubstituted benzo-fused (C₅-C₈)cycloalkane ring, L² is O,oxymethylene, or oxyethylene, M is benzene and X is para to L², X isCR¹R^(1′), R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³, R^(1′) isH, L³ is methylene, and A is CO₂H or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof. In some such embodiments, thecompound is a pharmaceutically acceptable salt or solvate thereof. Inother such embodiments, the compound is a prodrug which is, in someembodiments, an ester such as a (C₁-C₆)alkyl ester such as a methyl,ethyl, propyl, butyl, pentyl, or hexyl ester.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I.

In certain embodiments, the present invention provides a compound havingthe formula II or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof:

where Q,

L² and R¹ are as defined above with respect to formula I, and where R⁴,R⁵ and the subscripts n and p are defined below. In some suchembodiments, Q is selected from hydrogen, aryl, or heteroaryl;

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring;L² is selected from O or S(O)_(k); R¹ is selected from (C₂-C₈)alkynyl,aryl, heteroaryl, or —C(O)NR²R³; R² and R³ are independently selectedfrom hydrogen or (C₁-C₄)alkyl; and R⁴, R⁵, and the subscripts n and pare defined below.

In certain embodiments, L² is selected from O or S(O)_(k). In some suchembodiments, L² is —O—, —S— or —S(O)—; Q is aryl or heteroaryl; and

is cyclohexyl.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl or—C(O)NR²R³. In some embodiments, R¹ is a (C₂-C₈)alkynyl. In some suchembodiments, R¹ is a (C₃-C₈)alkynyl. In other embodiments, R¹ is anaryl. In still further embodiments, R¹ is a heteroaryl. In still otherembodiments, R¹ is a —C(O)NR²R³.

In certain embodiments, R¹ is selected from the group consisting ofprop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl,thiazolyl, thiophenyl, triazolyl, and —C(O)NR²R³. In some embodiments,R¹ is selected from a prop-1-ynyl. In other embodiments, R¹ is selectedfrom an imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl, thiazolyl,thiophenyl, or triazolyl. In other embodiments, R¹ is selected from a—C(O)NR²R³.

In certain embodiments, R² and R³ are independently selected fromhydrogen or (C₁-C₄)alkyl.

In certain embodiments where

is a substituted benzo-fused (C₅-C₈)cycloalkane ring, the one or moresubstituents, R⁴, is/are independently selected from the groupconsisting of substituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′,—NR′R″, —SR′, halogen, —OC(O)R″, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl and heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroups.

In some embodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring). In some such embodiments, R¹ is (C₂-C₈)alkynyl,aryl, heteroaryl or —C(O)NR²R³. In some embodiments, R¹ is a(C₂-C₈)alkynyl. In some such embodiments, R¹ is a (C₃-C₈)alkynyl. Inother embodiments, R¹ is an aryl. In still further embodiments, R¹ is aheteroaryl. In still other embodiments, R¹ is a —C(O)NR²R³.

In certain embodiments, R⁴ is independently selected from (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro.

The subscript n is 0, 1 or 2.

Each R⁵ is independently selected from the group consisting of(C₁-C₆)alkyl, halo(C₁-C₃)alkyl, hetero(C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, and nitro.

In some embodiments, R⁵ is independently selected from the groupconsisting of (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, and nitro.

The subscript p is 0, 1, 2, 3, or 4.

In certain embodiments, the subscript p is 0.

In some embodiments of formula II, Q is hydrogen,

is indane, the subscript p is zero, and R¹ is (C₂-C₃)alkynyl.

In other embodiments, Q is phenyl,

is indane, and R¹ is (C₂-C₃)alkynyl. In certain further embodiments, Qis a substituted phenyl, subscript p is zero, and L² is oxygen.

In some embodiments, L² is oxygen, the subscript n is 1, R⁴ isindependently selected from methyl, halogen, or (C₁-C₆)alkoxy, and R¹ is(C₂-C₃)alkynyl.

In certain embodiments, Q is hydrogen,

is tetrahydronaphthalene, L² is oxygen, and R¹ is (C₂-C₃)alkynyl.

It will be apparent that, in certain embodiments of formula II, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaIIa or IIb or a pharmaceutically acceptable salt, solvate, or prodrugthereof:

where Q,

L², R¹, R², R³, R⁴, R⁵ and the subscripts n and p have any of the valuesset forth above with respect to any of the embodiments of compounds offormula II. In some such embodiments, R¹ is (C₂-C₈)alkynyl, aryl,heteroaryl, or —C(O)NR²R³.

In some embodiments, the compound of formula II comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula II comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula II comprises a mixture of S— andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer or prodrug ofthe compound of formula II.

In some embodiments of formula II, the hydrogen on the carboxylic groupin formula II is replaced with an alkyl group to form an ester. Forexample, the compound of the present invention can be a methyl or ethylester of the compound of formula II.

In certain embodiments, the present invention provides a compound havingthe formula III or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof:

where Q,

L², R¹, R⁴ and the subscript n are as defined with respect to formula IIabove or any embodiments of compounds of formula II.

It will be apparent that, in certain embodiments of formula III, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaIIIa or IIIb or a pharmaceutically acceptable salt, solvate, or prodrugthereof:

where Q,

L², R¹, R², R³, R⁴ and the subscript n are as defined above in formulaII or in any embodiment thereof. In some such embodiments, R¹ is(C₂-C₈)alkynyl, aryl, heteroaryl, or —C(O)NR²R³.

In some embodiments, the compound of formula III comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula III comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula III comprises a mixture of S— andR-enantiomers.

In certain embodiments, the compound has the formula IV:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, L², R¹, R⁴, and the subscript n are as defined abovewith respect to formula II, and the subscript m is 1, 2, 3 or 4.

In some embodiments, the subscript m is 1 or 2.

In some embodiments, Q is hydrogen, L² is oxygen, the subscript n is 1or 2, R⁴ is independently selected from methyl, halogen or(C₁-C₆)alkoxy, and R¹ is (C₂-C₃)alkynyl.

As shown in formula IV, Q, L² and R⁴ (if one or more R⁴ groups arepresent) are attached to a benzo-fused cycloalkane ring. It will beunderstood that in various different embodiments, the attachments of Q,L² and R⁴ can be to any carbon of the benzo-fused cycloalkyl ring, asvalency permits.

In certain embodiments, the present invention provides astereoisomerically pure compound of formula IV. In some embodiments, thepresent invention provides a stereoisomerically mixed compound offormula IV.

In certain embodiments, the present invention provides a compound havingthe formula V:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, L², R¹, R⁴, and subscript n are as defined above withrespect to formula II.

It will be apparent that in certain embodiments of formula V, there aretwo chiral carbons. Thus, in some embodiments, the present inventionprovides a compound having formula Va, Vb, Vc, or Vd:

In some such embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl, or—C(O)NR²R³, and Q, L², R², R³, R⁴, and the subscript n are as definedabove with respect to formula II. In certain embodiments, the compoundof the invention is stereoisomerically pure. In some embodiments, thecompound of the invention is a mixture of two out of four stereoisomers.In other embodiments, the compound is a mixture of three out of fourstereoisomers. In yet other embodiments, the compound is a mixture ofall four stereoisomers.

In some embodiments, the present invention provides a compound havingthe formula VI:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, L², R¹, R⁴, and the subscript n are as defined abovewith respect to formula II.

In certain embodiments, the present invention provides astereoisomerically pure compound of formula VI. In some embodiments, thepresent invention provides a stereoisomerically mixed compound offormula VI.

In some embodiments, the present invention provides a compound havingthe formula VII:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, L², R¹, R⁴, and the subscript n are as defined abovewith respect to formula II.

In certain embodiments, the present invention provides astereoisomerically pure compound of formula VII. In some embodiments,the present invention provides a mixed stereoisomeric compound offormula VII.

In some embodiments, the present invention provides a compound havingthe formula X or XI:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, R⁴, and subscript n are as defined with respect toformula I or formula II above, and the subscript m is 1, 2, 3 or 4.

In certain embodiments, the present invention provides astereoisomerically pure compound of formula X or XI. In someembodiments, the A present invention provides a mixed stereoisomericcompound of formula X or XI.

In another aspect, the present invention provides a compound having theformula (I):

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)). In certain embodiments, L¹is a bond.

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring.In certain embodiments,

is a substituted cyclohexane ring or an unsubstituted cyclohexane ring.In certain embodiments,

is a benzo-fused (C₅-C₈)cycloalkane ring. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments,

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring).

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)) or (C₂-C₄)alkenylene-N(R^(b))SO₂, wherethe subscript k is 0, 1 or 2. In certain embodiments, L² is O orS(O)_(k), where the subscript k is 0, 1 or 2. In certain embodiments, L²is —O—, —S— or —S(O)—, where Q is aryl or heteroaryl, and

is cyclohexyl. In certain embodiments, L¹ is a bond and L² is —O—, —S—or —S(O)—. In certain embodiments, L² is —O—, —S— or —S(O)—, where Q isaryl or heteroaryl, and is cyclohexyl.

X is CR¹R^(1′).

L³ is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene, provided thatL³ is not a bond when L² is a bond. In some embodiments, L³ is a(C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene. In certain embodiments,L³ is (C₁-C₃)alkylene. In some embodiments, L³ is methylene. In certainembodiments, L³ is a methylene substituted with a monocyclic aryl ormonocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In certain embodiments,A is —CO₂H or a salt thereof. In some embodiments, A is —CO₂H or analkyl ester thereof. In some such embodiments, A is a C₁-C₆ alkyl estersuch as a methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃) alkyl, or(C₂-C₆)heteroalkyl. In certain embodiments, R^(a) is (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

M is a benzene ring, and R¹ is combined with M to form a 5-, 6- or7-membered benzo-fused cycloalkane ring containing 0, 1 or 2 heteroatomsselected from N, O and S. The following structures exemplify someembodiments where R¹ is combined with the adjacent benzene ring, i.e.,M, to form a benzo-fused cycloalkane ring:

where the dotted lines depict the sites of attachment to L² and L³ offormula I. In certain embodiments, M is a benzene ring substituted inaddition to where it is bonded to R¹. In some embodiments, M is abenzene ring that is bonded to R¹ but is otherwise unsubstituted.

In some embodiments, R¹ is combined with the adjacent benzene ring toform a 5-, 6- or 7-membered benzo-fused cycloalkane ring containing 0, 1or 2 heteroatoms selected from N, O and S. The following structures ofM-X-L³-A exemplify some embodiments where R¹ is combined with theadjacent benzene ring to form a benzo-fused cycloalkane ring:

where the dotted lines depict the sites of attachment to L² of formulaI, and the wavy bonds indicate that a chiral carbon is present. Incertain such embodiments, the compound can be a stereoisomerically purecompound. In some embodiments, the compound can be a mixture ofstereoisomers. In some embodiments, M is a benzene ring substituted inaddition to where it is bonded to R¹. In other embodiments, M is abenzene ring that is bonded to R¹ but is otherwise unsubstituted.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C8)alkynyl.

In some embodiments, R^(1′) is hydrogen or methyl.

In preferred embodiments, R^(1′) is hydrogen.

In some embodiments, the compound of formula I comprises astereomerically pure stereoisomer. In other embodiments, the compound offormula I comprises a mixture of stereoisomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I.

In some embodiments where M is a benzene ring, and R¹ is combined with Mto form a 5-, 6- or 7-membered benzo-fused cycloalkane ring, the presentinvention provides a compound having the formula VIII or IX:

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, where Q, L², R⁴, and subscript n are as defined with respect tocompounds of formula II, and the subscript m is 1, 2, 3 or 4.

In certain embodiments, the present invention provides astereoisomerically pure compound of formula VIII or IX. In someembodiments, the present invention provides a mixed stereoisomericcompound of formula VIII or IX.

In one aspect, the present invention provides a compound having theformula (I):

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond.

represents an optionally substituted (C₅-C₈)cycloalkane ring.

In certain embodiments, is a substituted cyclohexane ring, anunsubstituted cyclohexane ring, a substituted cyclopentane ring, or anunsubstituted cyclopentane ring.

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)) or (C₂-C₄)alkenylene-N(R^(b))SO₂, wherethe subscript k is 0, 1 or 2.

In certain embodiments, L² is O or S(O)_(k), where the subscript k is 0,1 or 2.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl, and

is cyclohexyl.

In certain embodiments, L¹ is a bond and L² is —O—, —S— or —S(O)—.

In certain embodiments, L² is —O—, —S— or —S(O)—, where Q is aryl orheteroaryl, and

is cyclohexyl.

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl.

In some embodiments, M is an aromatic ring or is a heteroaromatic ring.

In certain embodiments, M is a monocyclic aromatic, a monocyclicheteroaromatic ring, or a (C₅-C₈)cycloalkylene.

In some embodiments, M is an unsubstituted monocyclic aromatic ring oris an unsubstituted monocyclic heteroaromatic ring.

In certain embodiments, M is a substituted benzene ring.

In some embodiments, M is an unsubstituted benzene ring.

X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k), where the subscript k is 0,1, or 2.

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene, provided thatL³is not a bond when L² is a bond. In some embodiments, L³ is a(C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene.

In certain embodiments, L³ is (C₁-C₃)alkylene.

In some embodiments, L³ is methylene.

In certain embodiments, L³ is a methylene substituted with a monocyclicaryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl.

In certain embodiments, A is —CO₂H or a salt thereof.

In some embodiments, A is —CO₂H or an alkyl ester thereof. In some suchembodiments, A is a C₁-C₆ alkyl ester such as a methyl, ethyl, propyl,butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl.

In certain embodiments, R^(a) is (C₁-C₆)alkyl or (C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

R¹ is cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkyl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³. In some embodiments, R¹ is cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or—C(O)NR²R³.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl, or—C(O)NR²R³.

In certain embodiments, R¹ is a (C₂-C₈)alkynyl or a heteroaryl. In somesuch embodiments, R¹ is a (C₃-C₈)alkynyl. In other such embodiments, R¹is a heteroaryl.

In certain embodiments, R¹ is selected from the group consisting ofprop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl,thiazolyl, thiophenyl, triazolyl, and —C(O)NR²R³.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl.

In some embodiments, R^(1′) is hydrogen or methyl.

In preferred embodiments, R^(1′) is hydrogen.

In certain embodiments, R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl or—C(O)NR²R³, and R^(1′) is hydrogen.

R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl.

Optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached andincluding from 0 to 2 additional heteroatoms selected from N, O, or S.The ring formed by combining R² and R³ may be a saturated, unsaturated,or aromatic ring.

In some embodiments, the compound of formula I comprises astereomerically pure stereoisomer. In other embodiments, the compound offormula I comprises a mixture of stereoisomers.

In certain embodiments, L¹ is a bond, Q is H or aryl, represents anoptionally substituted cylopentane or cyclohexane ring, L² is O,oxymethylene, or oxyethylene, M is benzene and X is para to L², X isCR¹R^(1′), R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³, R^(1′) isH, L is methylene, and A is CO₂H or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof. In some such embodiments, thecompound is a pharmaceutically acceptable salt or solvate thereof. Inother such embodiments, the compound is a prodrug which is, in someembodiments, an ester such as a (C₁-C₆)alkyl ester such as a methyl,ethyl, propyl, butyl, pentyl, or hexyl ester.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I.

In certain embodiments, the compound of the present invention is acompound of formula II or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof, where Q is selected from hydrogen,aryl, or heteroaryl; represents an optionally substituted cycloalkanering; L² is selected from O or S(O)_(k); R¹ is selected from(C₂-C₈)alkynyl, aryl, heteroaryl, or —C(O)NR²R³; optionally, R¹ iscombined with the adjacent benzene ring to form a 5-, 6- or 7-memberedbenzo-fused cycloalkane ring containing 0, 1 or 2 heteroatoms selectedfrom N, O and S; R² and R³ are independently selected from hydrogen or(C₁-C₄)alkyl; R⁴ is independently selected from the group consisting ofsubstituted (C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, or and —NO₂, where R′, R″ and R′″ each independentlyrefer to hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; R⁵ is independently selected from the groupconsisting of (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; thesubscript k is 0, 1 or 2; the subscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, or 14; and the subscript p is 0, 1, 2, 3 or 4. Insome such embodiments, R⁴ is independently selected from (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or and nitro.

In one aspect, the present invention provides a compound having theformula XII or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where Q, L¹, P, L², M, X, L³, and A are defined below.

Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

In certain embodiments, Q is hydrogen, aryl, or heteroaryl.

In certain embodiments, Q is a substituted or unsubstituted phenyl.

L¹ is a bond, (C₁-C₄)alkylene, (C₂-C₄)heteroalkylene, O, S(O)_(k),N(R^(a)), C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b)).

In certain embodiments, L¹ is a bond. In some such embodiments, Q is H.

represents a benzo-fused (C₅-C₈)cycloalkane ring comprising a benzenering fused to a (C₅-C₈)cycloalkane ring, wherein the benzene ring of thebenzo-fused (C₅-C₈)cycloalkane ring is bonded to L² or M, if L² is abond. In some embodiments,

is a substituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments

is an unsubstituted benzo-fused (C₅-C₈)cycloalkane ring. In someembodiments where

is a benzo-fused (C₅-C₈)cycloalkane ring,

is selected from the group consisting of dihydroindene (i.e., indane ora benzo-cyclopentyl ring), tetrahydronaphthalene (i.e., abenzo-cyclohexyl ring), tetrahydrobenzo[7]annulene (i.e., abenzo-cycloheptyl ring), and hexahydrobenzo[8]annulene (i.e., abenzo-cyclooctyl ring).

L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂. In someembodiments, L² is selected from (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene,oxymethylene, O, or S(O)_(k). In some embodiments, L² is selected from—CH₂—O—, substituted oxymethylene, or O. In some embodiments, L² isselected from —CH₂—O— or —CH(CH₃)—O—. In some embodiments, L² isselected from —CH₂—O— or an alkyl-substituted oxymethylene. In certainembodiments, L² is O or S(O)_(k).

M is an aromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene or heteroaryl(C₁-C₄)alkylene. In certain embodimentswhere M is an aromatic ring, the term aromatic includes aryl. In otherembodiments where M is a heteroaromatic ring, the term heteroaromaticincludes heteroaryl. In some embodiments, M is an aromatic ring or is aheteroaromatic ring. In certain embodiments, M is a monocyclic aromaticor is a monocyclic heteroaromatic ring. In some embodiments, M is anunsubstituted monocyclic aromatic ring or is an unsubstituted monocyclicheteroaromatic ring. In certain embodiments, M is a substituted benzenering. In other embodiments, M is an unsubstituted benzene ring.

X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k), where the subscript k is 0,1, or 2. In some embodiments X is a CR¹R^(1′).

In certain embodiments, M is a substituted or unsubstituted benzene ringand X is para to L².

L³ is a (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene. In some embodiments,L³ is a (C₁-C₅)alkylene or is a (C₂-C₅)heteroalkylene. In certainembodiments, L³ is (C₁-C₃)alkylene. In some embodiments, L³ ismethylene. In certain embodiments, L³ is a methylene substituted with amonocyclic aryl or monocyclic heteroaryl.

A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl. In some embodiments, Ais —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃,thiazolidinedionyl, hydroxyphenyl, or pyridyl. In certain embodiments, Ais —CO₂H or a salt thereof. In some embodiments, A is —CO₂H or an alkylester thereof In some such embodiments, A is a C₁-C₆ alkyl ester such asa methyl, ethyl, propyl, butyl, pentyl, or hexyl ester.

R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃)alkyl, or(C₂-C₆)heteroalkyl. In certain embodiments, R^(a) is (C₁-C₆)alkyl or(C₂-C₆)heteroalkyl.

R^(b) is hydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl.

R¹ is cyano, aryl, heteroaryl, a heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³. In any ofthe embodiments described herein, the heterocycle of theheterocycloalkyl group of the R¹ group may be a saturated or unsaturatedheterocycloalkyl comprising from 5-7 ring members of which from 1-4 areheteroatoms selected from O, S, or N with the balance of the ringmembers being C. In certain embodiments, R¹ is selected from(C₂-C₈)alkynyl, aryl, heteroaryl, heterocycloalkyl, or —C(O)NR²R³. Insome embodiments, R¹ is selected from aryl, heteroaryl,heterocycloalkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)alkynyl. In other embodiments, R¹ is selected from R¹ is selectedfrom heteroaryl or heterocycloalkyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl;imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl;4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. Incertain embodiments, R¹ is selected from the group consisting ofprop-1-ynyl, phenyl, or a substituted or unsubstituted imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl,pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl,pyridyl, or pyrimidinyl.

R^(1′) is hydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, or (C₂-C₈)alkynyl. In some embodiments, R¹ is hydrogenor methyl. In some such embodiments, R^(1′) is hydrogen.

R^(1′) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C8)alkynyl, or (C₃-C₈)cycloalkyl.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl. Optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S. The ring formed by combining R² and R³ may be a saturated,unsaturated, or aromatic ring.

R² and R³ are independently selected from hydrogen, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl. Optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S. The ring formed by combining R² and R³ may be a saturated,unsaturated, or aromatic ring.

The subscript k is, in each instance, independently selected from 0, 1,or 2. In some embodiments, k is 0.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula I; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug of the tautomer; or amixture thereof.

In certain embodiments, the present invention provides a compound havingthe formula XIII or a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where Q is selected from hydrogen, aryl, or heteroaryl; L² is selectedfrom (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O, orS(O)_(k); R¹ is selected from (C₂-C₈)alkynyl, aryl, heteroaryl,heterocycloalkyl, or —C(O)NR²R³; R² and R³ are independently selectedfrom hydrogen or (C₁-C₄)alkyl; R⁴ is independently

selected from substituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′,—NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, or —NO₂, where R′, R″ and R′″ each independently refer tohydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl,aryl substituted with one to three halogens, unsubstituted alkyl, alkoxyor thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵is independently selected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,cyano, or nitro; the subscript k is 0, 1, or 2; the subscript n is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; and the subscript p is 0,1, 2, 3, or 4. In some such embodiments, R⁴ is independently selectedfrom (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro. In certainembodiments, is a benzo-fused (C₅-C₈)cycloalkane ring selected fromsubstituted or unsubstituted dihydroindene, tetrahydronaphthalene,tetrahydrobenzo[7]annulene, or hexahydrobenzo[8]annulene. In certainembodiments, R¹ is selected from 1-propynyl, substituted orunsubstituted phenyl, heteroaryl, or heterocycloalkyl. In some suchembodiments, R¹ is selected from substituted or unsubstitutedheteroaryl, or heterocycloalkyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiophenyl, furanyl, thiadiazolyl, pyridyl, orpyrimidinyl. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl;imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;tetrazol-5-yl; oxazol-2-yl; or dihydroisoxazol-3-yl. In some suchembodiments, R¹ is selected from a substituted or unsubstituted1-methyl-1H-imidazol-2-yl; 2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl; 3-methyl-3H-1,2,3-triazol-4-yl;1-methyl-1H-imidazol-5-yl; oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl;1-methyl-1H-tetrazol-5-yl; oxazol-2-yl; or 4,5-dihydroisoxazol-3-yl. Incertain embodiments, the subscript p is 0.

It will be apparent that, in certain embodiments of formula XIII, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaXIVA or XIVB or a pharmaceutically acceptable salt, solvate, or prodrugthereof or a tautomer, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula XIII comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula XIII comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula XIII comprises a mixture of S— andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula XIII; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula XIII, XIVA, and XIVB, the hydrogen on thecarboxylic group in formula XIII is replaced with an alkyl group to forman ester. For example, the compound of the present invention can be amethyl or ethyl ester of the compound of formula XIII.

In certain embodiments of the compound of formula XII, the compound hasthe formula XV or is a pharmaceutically acceptable salt, solvate,stereoisomer, or prodrug thereof; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof:

where R^(4′) is independently selected from substituted (C₁-C₆)alkyl,—R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′,—CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, or —NO₂, whereR′, R″ and R′″ each independently refer to hydrogen, unsubstituted(C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted withone to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; one of R⁶ and R^(6′) isL¹ or M, if L¹ is a bond, and the others of R⁶ and R^(6′) areindependently selected from H, (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy,cyano, or nitro; the subscript n′ is 0, 1, 2, or 3; and the subscript mis 1, 2, 3, or 4.

In some embodiments, the compound of formula XV comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula XV comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula XV comprises a mixture of S— andR-enantiomers.

In some embodiments, the compound of formula XV has the formula XVI:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

In some embodiments, the compound of formula XV or XVI, the compound hasthe formula XVII:

or is a pharmaceutically acceptable salt, solvate, stereoisomer orprodrug thereof; or a tautomer, or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof; or a mixture thereof.

It will be apparent that, in certain embodiments of formula XVII, thecarbon with a bond to R¹ is a chiral carbon. Thus, in certainembodiments, the present invention provides a compound having formulaXVIIA or XVIIB or a pharmaceutically acceptable salt, solvate, orprodrug thereof or a tautomer, or a pharmaceutically acceptable salt,solvate, or prodrug thereof; or a mixture thereof:

where the variables can have any of the values in any of the embodimentsdescribed above.

In some embodiments, the compound of formula XVII comprises astereomerically pure S-enantiomer. In other embodiments, the compound offormula XVII comprises a stereomerically pure R-enantiomer. In yet otherembodiments, the compound of formula XVII comprises a mixture of S— andR-enantiomers.

In certain embodiments, the compound of the present invention is apharmaceutically acceptable salt, solvate, stereoisomer, or prodrug ofthe compound of formula II; or a tautomer, or a pharmaceuticallyacceptable salt, solvate, stereoisomer, or prodrug thereof; or a mixturethereof.

In some embodiments of formula XV, XVI, XVII, XVIIA, and XVIIB, A is—CO₂H or is a salt thereof. In some embodiments, the hydrogen on thecarboxylic group of A is replaced with an alkyl group to form an ester.For example, the compound of the present invention can be a methyl orethyl ester of the compound of formula XV, XVI, XVII, XVIIA, or XVIIB.

In some embodiments of the compounds of formula XV, XVI, XVII, XVIIA,and XVIIB, the subscript m is 1 or 2.

In some embodiments of the compounds of formula XV, XVI, XVII, XVIIA,and XVIIB, the subscript m is 1 or 2; the subscript n′ is 0; L¹ is abond; L² is selected from —CH₂—O—, substituted oxymethylene, or O; R¹ isselected from aryl, heteroaryl, heterocycloalkyl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)alkynyl; R^(1′) is H; and A is—CO₂H.

In some embodiments of the compounds of formula XV, XVI, XVII, XVIIA,and XVIIB, Q is H; L³ is CH₂; and L² is —CH₂—O— or —CH(CH₃)—O—.

In some embodiments of the compounds of formula XV, XVI, XVII, XVIIA,and XVIIB, R⁶ and R^(6′) are independently selected from H and(C₁-C₆)alkyl and at least two of R⁶ and R^(6′) are (C₁-C₆)alkyl. In somesuch embodiments, R⁶ and R^(6′) are independently selected from H andmethyl and at least two of R⁶ and R^(6′) are methyl groups. In some suchembodiments, two of R⁶ and R^(6′) are methyl groups. In someembodiments, R⁶ and R^(6′) are independently selected from H and methyland at least four of R⁶ and R^(6′) are methyl groups. In some suchembodiments, R⁶ and R^(6′) are independently selected from H and methyland four of R⁶ and R^(6′) are methyl groups.

In some embodiments of the compounds of formula XII, XIII, XIV, XIVA,XIVB, XV, XVI, XVII, XVIIA, and XVIIB, R¹ is selected from heteroaryl orheterocycloalkyl. In some such embodiments, R¹ is selected from asubstituted or unsubstituted imidazolyl, triazolyl, tetrazolyl,oxazolyl, isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl,thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In certainsuch embodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl;or dihydroisoxazol-3-yl. In still further such embodiments, R¹ isselected from a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl.

In certain embodiments, the compound has the formula XVIIIA, XVIIIB,XVIIIC, or XVIIID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula XVIIIA, XVIIIB, XVIIIC,or XVIIID, has the formula XIXA, XIXB, XIXC, or XIXD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments, the compound of formula XIXA, XIXB, XIXC, orXIXD, has the formula XXA, XXB, XXC, or XXD:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula XVIIIA, XVIIIB,XVIIIC, XVIIID, XIXA, XIXB, XIXC, XIXD, XXA, XXB, XXC, or XXD, L² is—CH₂—O— or an alkyl-substituted oxymethylene; the subscript n′ is 0; R¹is (C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl; R^(1′) is H; and Ais —CO₂H. In some such embodiments, R¹ is selected from a substituted orunsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiophenyl, furanyl,thiadiazolyl, pyridyl, or pyrimidinyl. In some such embodiments, R¹ isselected from a substituted or unsubstituted imidazol-2-yl;1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl; ordihydroisoxazol-3-yl. In still further such embodiments, R¹ is selectedfrom a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some embodiments, the compound is acompound of formula XVIIIA. In some embodiments, the compound is acompound of formula XVIIIB. In some embodiments, the compound is acompound of formula XVIIIC. In some embodiments, the compound is acompound of formula XVIIID. In some embodiments, the compound is acompound of formula XIXA. In some embodiments, the compound is acompound of formula XIXB. In some embodiments, the compound is acompound of formula XIXC. In some embodiments, the compound is acompound of formula XIXD. In some embodiments, the compound is acompound of formula XXA. In some embodiments, the compound is a compoundof formula XXB. In some embodiments, the compound is a compound offormula XXC. In some embodiments, the compound is a compound of formulaXXD.

In certain embodiments, the compound of formula XXA, XXB, XXC, or XXD,has the formula XXIA, XXIB, XXIC, or XXID:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof; or atautomer or a pharmaceutically acceptable salt, solvate, or prodrugthereof; or a mixture thereof.

In certain embodiments of the compound of formula XXIA, XXIB, XXIC, orXXID, L² is —CH₂—O— or an alkyl-substituted oxymethylene; the subscriptn′ is 0; and R¹ is (C₂-C₃)alkynyl, heteroaryl, or heterocycloalkyl;R^(1′) is H. In some such embodiments, R¹ is selected from a substitutedor unsubstituted imidazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, dihydroisoxazolyl, pyrazolyl, pyrrolyl, thiazolyl,thiophenyl, furanyl, thiadiazolyl, pyridyl, or pyrimidinyl. In some suchembodiments, R¹ is selected from a substituted or unsubstitutedimidazol-2-yl; 1,2,4-triazol-3-yl; 1,2,3-triazol-4-yl; imidazol-5-yl;oxazol-5-yl; isoxazol-3-yl; pyrimidin-5-yl; tetrazol-5-yl; oxazol-2-yl;or dihydroisoxazol-3-yl. In still further such embodiments, R¹ isselected from a substituted or unsubstituted 1-methyl-1H-imidazol-2-yl;2-methyl-2H-1,2,4-triazol-3-yl; 4-methyl-4H-1,2,4-triazol-3-yl;3-methyl-3H-1,2,3-triazol-4-yl; 1-methyl-1H-imidazol-5-yl; oxazol-5-yl;isoxazol-3-yl; pyrimidin-5-yl; 1-methyl-1H-tetrazol-5-yl; oxazol-2-yl;or 4,5-dihydroisoxazol-3-yl. In some embodiments, the compound is acompound of formula XXIA. In some embodiments, the compound is acompound of formula XXIB. In some embodiments, the compound is acompound of formula XXIC. In some embodiments, the compound is acompound of formula XXID.

5.2.2 Preparation of the Compounds

The compounds of the invention can be prepared by a variety of syntheticor semisynthetic techniques. Scheme 1 provides a general syntheticscheme for exemplary compounds of the invention utilizing ester A inwhich the benzene ring may be substituted or unsubstituted with R⁵groups as defined herein. Methods 1-14 below provide syntheses of Abearing different exemplary R¹ groups. Additional examples for thesynthesis of esters of formula A are provided below and describesynthetic routes to exemplary compounds provided herein. Furtherrelevant synthetic routes for related compounds are described in WO2005/086661 and US 2006/0004012 which are both hereby incorporated byreference in their entireties and for all purposes as if fully set forthherein. Appropriate starting materials can be prepared by techniquesknown or apparent to those of skill in the art or the starting materialsmay be commercially available. One of skill in the art will understandthat the synthetic routes can be modified to use different startingmaterials or alternative reagents and that suitable adjustments inconditions (e.g., temperatures, solvents, etc.) can be made toaccomplish the desired transformations. Additionally, one of skill inthe art will recognize that protecting groups may be necessary for thepreparation of certain compounds and will be aware of those conditionscompatible with a selected protecting group. Examples of such protectinggroups include, for example, those set forth in Protective Groups inOrganic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, NewYork, N.Y., (3rd Edition, 1999). Accordingly, the exemplary methods andthe examples described herein are illustrative of the present inventionand are not to be construed as limiting the scope thereof.

Scheme 2 shows a general synthetic route that can be used to preparecompounds of formula XXIV and XXV, and salts thereof. In the compound offormula XXII and XXIV, Alk is a straight or branched chain alkyl grouphaving from 1 to 8 carbon atoms. Examples of such groups include methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, i-propyl, s-butyl,t-butyl groups, and the like. In some embodiments, Alk is a methyl orethyl group. In the compounds of formula XXII, XXIV and XXV, R¹ is anyof the R¹ groups described herein. For example, R¹ may be selected fromcyano, aryl, heteroaryl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)alkynyl, or C(O)NR²R³ where R² and R³ have the same values as setforth with respect to any of the compounds of any of the embodiments setforth herein. In the compounds of formula XXIII, XXIV, and XXV, R⁴ isindependently selected from substituted (C₁-C₆)alkyl, —R′, ═O, —OR′, ═O,═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, or —NO₂, where R′, R″ and R′″each independently refer to hydrogen, unsubstituted (C₁-C₈)alkyl orheteroalkyl, unsubstituted aryl, aryl substituted with one to threehalogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; m is selected from 1, 2,3, or 4; n is selected from 0, 1, or 2; and Y is selected fromsubstituted (C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,halogen, —OC(O)R′, -C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroup. In the compound of formula XXIII W represents a leaving groupsuch as a halogen like Br or Cl, an OH, a tosylate, mesylate, or thelike. Coupling of a compound of formula XXII with a compound of formulaXXIII may be accomplished using different procedures. For example, whenW is a halogen such as Br, Cl, or I (conveniently synthesized from theother two using the Finkelstein reaction as known to those skilled inthe art), then a compound of formula XXII may be coupled with a compoundof formula XXIII by reacting the two in the presence of any appropriatebase such as, but not limited to, Cs₂CO₃ in an appropriate solvent suchas, but not limited to DMF. When W is an OH, then a compound of formulaXXII may be coupled with a compound of formula XXIII using anazodicarboxylate such as DEAD, TMAD, or DIAD in combination with asuitable phosphine such as a trialkylphosphine, a triarylphosphine, analkyldiarylphosphine, or a dialkylarylphosphine. This highly flexibleapproach allows a large number of compounds of formula XXIV to besynthesized and then converted to compounds of formula XXV by removal ofthe ester functionality. Conversion of a compound of formula XXIV to acompound of formula XXV may be accomplished by reacting the compound offormula XXIV with a metal hydroxide base such as, but not limited to,LiOH, NaOH, KOH, Ca(OH)₂, or the like. When Y is a halogen such as abromine in compounds of formula XXIV, then reaction with a boronic acidcompound such as an aryl-B(OH₂) or alkyl-B(OH)₂ compound using Suzukiconditions as described herein can be used to add a substituted orunsubstituted aryl group in place of Y in the compounds of formula XXIVwhich may then be cleaved to provide a compound of formula XXV where Yis an optionally substituted aryl group. Those skilled in the art willrecognize that the carbon atom bonded to R¹ in compounds of formulaXXII, XXIV, and XXV is a chiral center. In accordance with the methoddescribed above, XXII, XXIV, and XXV may be a mixture of the R and Senantiomers, may be the R enantiomer, or may be the S enantiomer.Therefore, in some embodiments each of the compounds of formula XXII,XXIV, and XXV are a mixture of the R and S enantiomers. In otherembodiments, each of the compounds of formula XXII, XXIV, and XXV arethe R enantiomer. In other embodiments, each of the compounds of formulaXXII, XXIV, and XXV are the R enantiomer.

In one aspect, the invention provides a method of synthesizing acompound of formula XXIV.

The method includes: reacting a compound of formula XXII with a compoundof formula XXIII to produce the compound of formula XXIV, wherein thecompounds of formula XXII and XXIII have the following structures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, orC(O)NR²R³; R² and R³ are independently selected from hydrogen, aryl,heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl; or optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S; R⁴ is independently selected from substituted (C₁-C₆)alkyl,—R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, or —NO₂, whereinR′, R″ and R′″ are each independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ isindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro; p is 0, 1, 2, 3, or 4; m is 1,2, 3, or 4; n is 0, 1, or 2; Y is selected from substituted(C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroup; W is a leaving group; and further wherein, the compounds offormula XXII and XXIV can be a mixture of compounds having the R and Sstereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.

In some embodiments, W is selected from OH, a halogen, a group offormula OTs, OMs, or OTf where Ts is p-toluenesulfonyl, Ms isMethanesulfonyl, and Tf is trifluoromethanesulfonryl (OTs is tosylate,OMs is mesylate, and OTf is triflate). In some such embodiments, W is OHand a phosphine selected from a trialkylphosphine, adialkylarylphosphine, an alkyldiarylphosphine, or a triarylphosphine andan azodicarboxylate are used to react the compound of formula XXII withthe compound of formula XXIII. In other such embodiments, W is a halogenselected from Br or Cl, and a base is used to react the compound offormula XXII with the compound of formula XXIII.

In some embodiments, Alk is selected from methyl or ethyl.

In some embodiments, m is 1 or 2.

In some embodiments, n is 0.

In some embodiments, p is 0.

In some embodiments, Y is a halogen, and the method further comprisesreacting the compound of formula XXIV with a boronic acid compound. Insome such embodiments, the boronic acid compound has the formulaaryl-B(OH)₂ or alkyl-B(OH)₂.

In some embodiments, the method further includes removing the Alk groupof the compound of formula XXIV to form a compound of formula XXV or asalt thereof, and the compound of formula XXV has the followingstructure:

wherein Y, R⁴, n, m, R⁵, p, and R¹ have the definitions provided withrespect to the compounds of any of the embodiments of formula XXII,XXIII, and XXIV. In some such embodiments, the compound of formula XXIVis reacted in the presence of a hydroxide base to produce the compoundof formula XXV. In some such embodiments, the hydroxide base is selectedfrom LiOH, NaOH, KOH, or Ca(OH)₂.

5.2.3 Compositions

In another aspect, the invention provides pharmaceutical compositionssuitable for pharmaceutical use comprising one or more compounds of theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients (and in the specified amounts, ifindicated), as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. By “pharmaceutically acceptable” it is meant that thecarrier, excipient, or diluent is compatible with the other ingredientsof the formulation and is not deleterious to the recipient thereof.

Composition formulation may improve one or more pharmacokineticproperties (e.g., oral bioavailability, membrane permeability) of acompound of the invention (herein referred to as the active ingredient).

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art. All methodsinclude the step of bringing the active ingredient into association withthe carrier which constitutes one or more accessory ingredients. Ingeneral, the pharmaceutical compositions are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation. In thepharmaceutical composition, the active object compound is included in anamount sufficient to produce the desired effect upon the process orcondition of diseases.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions. Suchcompositions may contain one or more agents selected from sweeteningagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with other non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid, or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated by the techniques described in U.S. Pat. Nos. 4,256,108,4,160,452, and 4,265,874 to form osmotic therapeutic tablets for controlrelease.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil, orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin, or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, and flavoring and coloringagents.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose, any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The pharmaceutical compositions may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include, for example, cocoa butter and polyethyleneglycols.

For topical use, creams, ointments, jellies, solutions, or suspensions,etc., containing the compounds of the invention are employed. As usedherein, topical application is also meant to include the use ofmouthwashes and gargles.

The pharmaceutical compositions and methods of the invention may furthercomprise other therapeutically active compounds, as noted herein, usefulin the treatment of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

5.2.4 Methods of Use

In another aspect, the invention provides methods of treating orpreventing a disease or condition selected from the group consisting oftype II diabetes, obesity, hyperglycemia, glucose intolerance, insulinresistance, hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema,comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound or composition of the invention.

In one embodiment, the disease or condition is type II diabetes.

In another aspect, the present invention provides a method for treatinga disease or condition responsive to the modulation of GPR40 comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound or composition of the invention.

In some embodiments, the disease or condition is selected from the groupconsisting of type II diabetes, obesity, hyperglycemia, glucoseintolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer and edema.

In certain embodiments, the disease or condition is type II diabetes.

In some embodiments, the disease or condition is obesity.

In some embodiments, the disease or condition is hypertension.

In some embodiments of administering the compounds or compositions ofthe invention, the compound or composition is administered orally.

In other embodiments, the compound or composition is administeredparenterally.

In other embodiments, the compound or composition is administered incombination with a second therapeutic agent.

In other embodiments, the second therapeutic agent is an insulinsensitizing agent, such as metformin or a thiazolidinedione, forexample.

In another aspect, the invention provides methods of treating orpreventing a disease or disorder responsive to modulation of GPR40comprising administering to a subject having such a disease or disorder,a therapeutically effective amount of one or more of the subjectcompounds or compositions.

In yet another aspect, the invention provides methods of treating orpreventing a GPR40-mediated condition, disease or disorder comprisingadministering to a subject having such a condition, disease or disorder,a therapeutically effective amount of one or more of the subjectcompounds or compositions.

In yet another aspect, the invention provides methods of modulatingGPR40 comprising contacting a cell with one or more of the subjectcompounds or compositions.

For example, in some embodiments, a cell that constitutively expressesGPR40 is contacted with one or more of the subject compounds orcompositions.

In certain embodiments, a cell to be contacted can be made to express oroverexpress GPR40, for example, by expressing GPR40 from heterologousnucleic acid introduced into the cell or, as another example, byupregulating the expression of GPR40 from nucleic acid endogenous to thecell.

Depending on the disease to be treated and the subject's condition, thecompounds of the invention may be administered by oral, parenteral(e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection or implant), inhalation,nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal,local) routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The invention alsocontemplates administration of the compounds of the invention in a depotformulation, in which the active ingredient is released over a definedtime period.

In the treatment or prevention type II diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome,syndrome X, cardiovascular disease, atherosclerosis, kidney disease,ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy,diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia,hypoglycemia, cancer and edema or other conditions or disordersassociated with GPR40, an appropriate dosage level will generally beabout 0.001 to 100 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.01 to about 25 mg/kg per day; more preferably about 0.05to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5mg/kg per day. Within this range, the dosage may be 0.005 to 0.05, 0.05to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, thecompositions are preferably provided in the form of tablets containingfrom 1.0 to 1000 milligrams of the active ingredient, particularly 1.0,3.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0,250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated. The compounds may beadministered on a regimen of 1 to 4 times per day, preferably once ortwice per day.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general health, sex, diet, mode and timeof administration, rate of excretion, drug combination, the severity ofthe particular condition, and the host undergoing therapy.

The compounds of the invention can be combined or used in combinationwith other agents useful in the treatment, prevention, suppression oramelioration of the diseases or conditions for which compounds of theinvention are useful, including type II diabetes, obesity,hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.Such other agents, or drugs, may be administered, by a route and in anamount commonly used therefore, simultaneously or sequentially with acompound of the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe invention is preferred. Accordingly, the pharmaceutical compositionsof the invention include those that also contain one or more otheractive ingredients or therapeutic agents, in addition to a compound ofthe invention.

The compounds of the invention may be used in combination with a secondtherapeutic agent such as those described herein. Thus, in someembodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of a subject with a disease or condition mediated by GPR40. Insome embodiments, therapeutic compositions are provided that include acompound of the invention and a second therapeutic agent as a combinedpreparation for simultaneous, separate or sequential use in theprophylactic treatment of a subject at risk for a disease or conditionmediated by GPR40. In some such embodiments, the components are providedas a single composition. In other embodiments, the compound and thesecond therapeutic agent are provided separately as parts of a kit.

Examples of other therapeutic agents that may be combined with acompound of the invention, either administered separately or in the samepharmaceutical compositions, include, but are not limited to: (a)cholesterol lowering agents such as HMG-CoA reductase inhibitors (e.g.,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin andother statins), bile acid sequestrants (e.g., cholestyramine andcolestipol), vitamin B₃ (also known as nicotinic acid, or niacin),vitamin B₆ (pyridoxine), vitamin B₁₂ (cyanocobalamin), fibric acidderivatives (e.g., gemfibrozil, clofibrate, fenofibrate andbenzafibrate), probucol, nitroglycerin, and inhibitors of cholesterolabsorption (e.g., beta-sitosterol and acylCoA-cholesterolacyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthaseinhibitors, squalene epoxidase inhibitors and squalene synthetaseinhibitors; (b) antithrombotic agents, such as thrombolytic agents(e.g., streptokinase, alteplase, anistreplase and reteplase), heparin,hirudin and warfarin derivatives, p-blockers (e.g., atenolol),β-adrenergic agonists (e.g., isoproterenol), ACE inhibitors andvasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride,nitroglycerin and enaloprilat); and (c) anti-diabetic agents such asinsulin and insulin mimetics, sulfonylureas (e.g., glyburide,meglinatide), biguanides, e.g., metformin (GLUCOPHAGE®), α-glucosidaseinhibitors (acarbose), insulin sensitizers, e.g., thiazolidinonecompounds, rosiglitazone (AVANDIA®), troglitazone (REZULIN®),ciglitazone, pioglitazone (ACTOS®) and englitazone, DPP-IV inhibitors,e.g., vildagliptin (Galvus®), sitagliptin (Januvia™), and GLP-I analogs,e.g., exenatide (Byetta®). In some embodiments, a compound of theinvention may be administered along with a DPP-IV inhibitor or a GLP-Ianalog.

The weight ratio of the compound of the invention to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used.Combinations of a compound of the invention and other active ingredientswill generally also be within the aforementioned range, but in eachcase, an effective dose of each active ingredient should be used.

In another aspect, the present invention provides a method formodulating circulating insulin concentration in a subject, comprisingadministering a compound or composition of the invention.

In some embodiments, the insulin concentration is increased.

In other embodiments, the insulin concentration is decreased.

The following examples are offered by way of illustration and are notintended to limit the scope of the invention. Those of skill in the artwill readily recognize a variety of noncritical parameters that could bemodified to yield essentially similar results.

6. EXAMPLES

Unless otherwise stated, all compounds were obtained from commercialsources or were prepared using the methods and experimental proceduresdescribed herein. Various procedures are also set forth in publishedU.S. patent application No. 2006/0004012 which is hereby incorporated byreference in its entirety and for all purposes as if set forth herein.The following abbreviations are used to refer to various reagents,solvents, experimental procedures, or analytical techniques that aredescribed in the examples:

ACN Acetonitrile

AcOH Acetic Acid

DCM Dichloromethane

DEAD Diethylazodicarboxylate

DIAD Diisoprolylazodicarboxylate

DMF N,N′-Dimethyl Formamide

DMSO Dimethyl Sulfoxide

ESI Electrospray Ionization

EtOAc EtOAc

EtOH Ethanol

HPLC High Performance Liquid Chromatography

HSA Human Serum Albumin

i-PrOH 2-Propanol

LDA Lithium Diisopropylamide

MeOH Methanol

MS Mass Spectrometry

NBS N-Bromosuccinimide

n-BuLi n-butyllithium

NMR Nuclear Magnetic Resonance

n-PrOH 1-Propanol 9

PCC Pyridinium Chlorochromate

PDC Pyridinium Dichromate

PPTS Pyridinium p-Toluenesulfonate

SPA Scintillation Proximity Assay

t-BuOH t-Butanol

TEA Triethylamine

THF Tetrahydrofuran

TFA Trifluoroacetic Acid

TLC Thin Layer Chromatography

TMAD N,N,N′,N′-Tetramethylazodicarboxamide

5-(4-Hydroxy-benzylidene)-2,2-dimethyl-[1,3]dioxane-4,6-dione (M1.1).Condensation with Meldrum's acid was carried out according to the methodof Bigi et. al. (2001) Tetrahedron Lett. 42:5203-5205. A 2 L pear-shapedflask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water(400 mL). The flask was placed in a water bath at 75° C., and Meldrum'sacid (62 g, 430 mmol) was added as a slurry in 400 mL of water. Thereaction mixture was agitated for 2 hours and cooled in an ice bath for2 hours. The product was collected by filtration and rinsed with coldwater. After drying thoroughly, adduct M1.1 was obtained as a fineyellow powder. MS ESI (pos.) m/e: 519.0 (2M+Na). ¹H NMR (500 MHz)(DMSO-d₆) δ 9.75 (br s, 1H); 8.27 (s, 1H); 8.24 (d, 2H, J=10 Hz); 6.98(d, 2H, J=10 Hz);.1.76 (s, 6H).

(±)-5-[1-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-[1,3]dioxane-4,6-dione(M1.2). An oven-dried 3 L 3-neck flask was equipped with a mechanicalstirrer, a nitrogen inlet, and a nitrogen outlet and placed in aroom-temperature water bath. After purging with nitrogen for 20 minutes,a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) wasadded by cannula. In a separate oven-dried and nitrogen-flushed 500 mLround-bottom flask, compound M1.1 (35 g, 142 mmol) was dissolved inanhydrous THF (350 mL) with gentle warming. The solution of M1.1 wasadded over 15 minutes. Over the course of the addition, the reactionmixture changed to a thick, yellow suspension. After the addition wascomplete, the reaction mixture was stirred for 15 minutes, quenched withaqueous NH₄Cl (0.6 N, 750 mL), and diluted with hexanes (800 mL). Thelayers were separated, and the organic layer was discarded. The aqueouslayer was acidified to pH ˜2 with saturated aqueous KHSO₄ and extractedwith EtOAc (2×400 mL). The combined extracts were washed with saturatedbrine, dried over MgSO₄, filtered, and concentrated to a light yellowsolid. MS ESI (pos.) m/e: 599.0 (2M+Na). ¹H NMR (500 MHz) (acetone-d₆) δ8.26 (s, 1H); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (brs, 1H); 4.46 (d, 1H, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s,3H).

(±)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (M1.3). A 1 L round-bottomflask was charged with compound M1.2 (37 g), diethyl ketone (160 mL),and water (80 mL). The suspension was heated at reflux for 48 hours.After cooling, the aqueous layer was saturated with NaCl(s) andseparated. The organic layer was dried over MgSO₄, filtered, andconcentrated to a light brown oil, which was crystallized from hotEtOAc:hexanes (1:2). After collecting and drying, the product wasobtained as an off-white powder. MS ESI (pos.) m/e: 205.1 (M+H); 227.1(M+Na). ¹H NMR (500 MHz) (DMSO-d₆) δ 12.2 (s, 1H); 9.27 (s, 1H); 7.12(d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, 1H); 2.54 (m, 2H);1.82 (d, 3H, J=2.4 Hz).

(3S)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (M1.4). A 5 L round-bottomflask was charged with compound M1.3 (66.4 g, 325 mmol) and i-PrOH (1 L)and heated to 70° C. (IS, 2R)-1-Amino-2-indanol (46.1 g, 309 mmol) wasdissolved in i-PrOH (1 L) with gentle warming. The solution of amine wasadded to the dissolved carboxylic acid and the resulting solution wasallowed to cool to room temperature. After 16 hours, the crystals werecollected and dried. The salt was re-suspended in 2 L of i-PrOH anddissolved by heating to reflux. After allowing to cool to roomtemperature, the salt was collected after 16 hours. A small sample ofthe salt was decomposed with aqueous acid and the free carboxylic acidwas analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1%TFA in 90:10 hexanes:i-PrOH) and was found to have 75% ee. The salt wasre-suspended in 1.5 L of i-PrOH and dissolved by heating to reflux.After allowing to cool to room temperature, the salt was collected after16 hours. This material was found to have 96% ee by chiral HPLC. Thismaterial was suspended in EtOAc (300 mL) and water (100 mL). Saturatedaqueous KHSO₄ (100 mL) was added with vigorous mixing. After two clearlayers were obtained, the layers were separated, and the aqueous layerwas extracted with EtOAc (100 mL). The combined extracts were washedwith saturated brine, dried over MgSO₄, filtered, and concentrated to alight yellow oil, which crystallized on drying in vacuo. Compound M1.4was obtained as an off-white solid.

(3S)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (M1). PhenolM1.4 (23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treatedwith KHCO₃ (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80mmol) was added, and the reaction was stirred at 40° C. for 14 hours. Anadditional portion of methyl iodide (3 mL, 48 mmol) was added andheating was continued for 24 hours. Potassium salts were removed byfiltration and thoroughly rinsed with acetone. The filtrate wasconcentrated to an oil, which was filtered through a 1 cm plug of silicagel. Elution with 2.5% MeOH in DCM followed by concentration providedphenol 1 as a light yellow oil. MS ESI (pos.) m/e: 219.1 (M+H); 241.1(M+Na). ¹H NMR (500 MHz) (acetone-d₆) δ .2 (br s, 1H); 7.20 (d, 2H,J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, 1H); 3.60 (s, 3H), 2.65 (m,2H); 1.78 (d, 3H, J=2.5 Hz).

Ethyl 3-(4-fluoro-phenyl)-3-(4-hydroxy-phenyl)-acrylate (M2.1). Asolution of lithium hexamethyldisilazide (23.1 mL, 1 M in THF) was addedto a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9mmol) in THF (15 mL) in 10 minutes at ˜78° C. The reaction mixture wasfurther stirred at this temperature for 20 minutes. A solution of(4-fluoro-phenyl)-(4-hydroxy-phenyl)-methanone (2 g, 9.2 mmol) in THF(30 mL) was slowly added to the reaction mixture. The reaction mixturewas brought to 0° C. over 5 hours. The reaction mixture was quenchedwith saturated ammonium chloride solution, extracted into EtOAc andwashed with dilute ammonium chloride solution. The organic layer wasdried over magnesium sulfate. The solvent was removed under vacuum, andthe resulting product was flash chromatographed on silica gel, givingM1.1 as an oil.

(±)-3-(4-Fluoro-phenyl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester(M2). A solution of M2.1 (385 mg) in EtOH (12 mL) and EtOAc (10 mL) wasstirred with 10% Pd—C (50 mg) under a hydrogen atmosphere at roomtemperature for 3 hours. The reaction mixture was filtered andconcentrated to provide M2.

6.3 Method 3

Starting from (4-hydroxy-phenyl)-phenyl-methanone, compound M3 wasprepared according to methods analogous to those described in Method 2.

2,2-Dimethyl-5-[4-(tetrahydro-pyran-2-yloxy)-benzylidene]-[1,3]dioxane-4,6-dione(M4.1). Protection of the phenol with dihydropyran was carried out basedon the method described in Miyashita et al. (1977) J. Org Chem. 42:3772.Compound M1.1 (500 g, 2 mol) was dissolved in DCM (4 L).3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followedby PPTS (5 g, 20 mmol). The reaction mixture was then heated at a gentlereflux (3.5 hours). The reaction was concentrated under reduced pressureto ˜2 L of volume. 1 L of acetone was then added, and 2 L of solventwere removed under reduced pressure. 1 L of acetone was added, and 1 Lof solvent was removed under reduced pressure. 0.5 L of acetone wasadded, and 0.5 L of solvent was removed under reduced pressure. Theresulting slurry of very fine, light yellow crystals was filtered andrinsed sequentially with two 500 mL portions of acetone. The product wasdried in a vacuum oven at 50° C. until no further solvent collected inthe traps. Compound M4.1 was obtained as fine, light yellow crystals. MSESI (pos.) m/e: 355.1 (M+Na). ¹H NMR (400 MHz) (DMSO-d₆) δ 8.29 (s, 1H);8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz);. 5.67 (m, 1H); 3.70 (m,1H); 3.60 (m, 1H).1.9-1.5 (m, 12H).

(±)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate (M4). A 500mL flask was equipped with a magnetic stir bar, a nitrogen inlet, and anitrogen outlet and placed in a room-temperature water bath. CompoundM4.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF(150 mL). After purging with nitrogen for 30 minutes, a solution ofthiophene-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added bycannula. After the addition was complete, the reaction mixture wasstirred for 1.5 hours and quenched with aqueous NH₄Cl (1 M, 100 mL), anddiluted with EtOAc (100 mL). The aqueous layer was acidified to pH ˜2with concentrated HCl and extracted with EtOAc (150 mL×2). The extractwas washed with brine and concentrated. The residue was dissolved in 100mL of 10:1 DMF:water and heated to 100° C. for 8 hours. The reaction wascooled, diluted with 500 mL water, and extracted with EtOAc (150 mL×3).The organic layer was dried with MgSO₄, filtered, and concentrated on arotary evaporator. The residue was dissolved in MeOH (200 mL), 5 dropsof concentrated H₂SO₄ were added, and the solution was refluxed for 24hours. The solution was concentrated to a residue on a rotary evaporatorand flash column chromatographed with 30% EtOAc/hexanes as the eluant.The fractions were combined and concentrated to afford M4 as a viscousoil.

2-(4-(Benzyloxy)phenyl)-N-(prop-2-ynyl)acetamide (M5.1). A mixture of4-(benzyloxy)phenylacetic acid (20.7 mmol), 1-hydroxybenzotrizolehydrate (37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37mmol), propargylamine (20.7 mmol) and N-methylmorpholine (62 mmol) inDMF (60 mL) were stirred at room temperature overnight. The reactionmixture was diluted with EtOAc (400 mL), washed with 1N HCl, water,saturated Na₂CO₃ solution, and brine, and dried over Na₂SO₄. Afterremoving solvent under reduced pressure, the residue was triturated withDCM. Compound M5.1 was obtained as a white solid after filtration anddrying. LC-MS ESI (pos.) m/e: 280 (M+H).

2-(4-Benzyloxy)benzyl)-5-methyl oxazole (M5.2). A mixture of compoundM5.1 (10.1 mmol) and AuCl₃ (1 mmol) in DCM (100 mL) was stirred at roomtemperature overnight. Additional DCM (100 mL) was added, and thereaction mixture was washed with NaHCO₃ solution and saturated brine.After drying over Na₂SO₄ and concentration under reduced pressure, theresidue was column chromatographed (1:2 EtOAc:hexanes) to obtaincompound M5.2. LC-MS ESI (pos.) m/e: 280 (M+H).

(±)-Ethyl 3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate(M5.3). To a solution of 2-(4-(benzyloxy)benzyl)-5-methyloxazole (M5.2)(3.23 mmol) in THF (25 mL) at −78° C., was added dropwise LDA (4.5mmol). The mixture was stirred for 18 minutes, followed by addition ofethyl bromoacetate (4.5 mmol). It was allowed to warm to roomtemperature for 3 hours, followed by addition of water, which wasextracted with EtOAc. The extract was washed with brine and dried overNa₂SO₄ using standard work up conditions. Column chromatography (⅓EtOAc/hexane) of the residue afforded compound M5.3. MS ESI (pos.) m/e:366 (M+H).

(±)-Ethyl 3-(4-hydroxyphenyl)-3-(5-methyloxazol-2-yl)propanoate (M5). Amixture of ethyl3-(4-(benzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate (M5.3) (2.47mmol) and Pd—C (270 mg) in EtOH was stirred under hydrogen atmosphere atroom temperature for 4 hours. The Pd—C was removed by filtration throughsilica gel eluting with EtOH. After concentration, product M5 wasobtained. MS ESI (pos.) m/e 276 (M+H).

(±)(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(M6.1). 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M inTHF, 35 mL, 17.5 mmol) was added to a solution of3,5-difluorobenzaldehyde (1.95 g, 13.7 mmol) in THF (50 mL) slowly viasyringe at −78° C. The reaction mixture was stirred at this temperaturefor 3 hours and then quenched with saturated NH₄Cl (aqueous). Themixture was extracted with EtOAc (60 mL×2), and the combined organiclayers were dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide a colorless oil (3.9 g) as product M6.1, which wasused directly in the next step.

(±)-(3,5-Difluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(M6.2). PDC (8.5 g, 22.6 mmol) was added to the solution of M6.1 (3.9 g,13.7 mmol) in DCM (100 mL) at 0° C. in several portions. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 6 hours. Silicagel (about 20 g) was added to the reaction mixture and the resultingslurry was filtered through a pad of silica gel to remove most of theinorganic chemicals. The solid was washed with DCM until no furtherproduct remained on the silica gel (monitored by TLC). The combinedorganic solvent was washed with water and saturated brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to provide anoily residue, which was flash chromatographed (silica gel, 0-30% EtOAcin hexane), generating product ketone M6.2 as light yellow oil. MS ESI(pos.) m/e: 319 (M+H).

(Z/E)-Ethyl3-(3,5-difluorophenyl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M6.3). Ethyl(trimethylsilyl)acetate (2.63 g/3.0 mL in 20 mL THF) wasadded to lithium hexamethyldisilazide (1 M in THF, 17.6 mL) at −78° C.slowly via syringe. The mixture was stirred at the same temperature for1 hour, and the solution of ketone M6.2 (4.3 g, 13.5 mmol) in anhydrousTHF (25 mL) was added slowly via syringe. The reaction mixture wasfurther stirred at this temperature for 2 hours. The reactiontemperature was then allowed to rise to −20° C. in 6 hours. The reactionmixture was quenched with saturated ammonium chloride (aqueous) at thistemperature, extracted with EtOAc (2×100 mL) and dried over Na₂SO₄.After filtration, the solvent was removed under reduced pressure andM6.3 was obtained as light yellow oil (including some ethyl(trimethylsilyl)acetate), which was used directly in the next step. MSESI (pos.) m/e: 389 (M+H).

(±)-Ethyl 3-(3,5-difluorophenyl)-3-(4-hydroxyphenyl)propanoate (M6). Asolution of olefin M6.3 (5.4 g, 13.5 mmol) in EtOH (80 mL) was stirredwith 10% Pd—C (1.5 g, 1.4 mmol) under a hydrogen atmosphere (provided bya balloon) overnight at room temperature. The reaction mixture wasfiltered through a short silica gel pad and stirred with AcOH (14 mL) atroom temperature for 4 hours. The reaction mixture was concentratedunder reduced pressure to provide a yellow oily residue, which wasre-dissolved in DCM (150 mL) and washed with water, saturated NaHCO₃,water, and brine, and dried over Na₂SO₄. After filtration, the solventwas removed under reduced pressure, and the residue was flashchromatographed (silica gel, 0-40% EtOAc in hexane as eluant). Theproduct (±)ethyl ester M6. MS ESI (pos.) m/e: 307 (M+H).

(±)-Ethyl 3-(2,4-difluoro-phenyl)-3-(4-hydroxy-phenyl)propanoate (M7).Compound M7 was prepared by a method analogous to that for M6.

(±)-Ethyl 3-(2,5-difluoro-phenyl)-3-(4-hydroxy-phenyl)propanoate (M8).Compound M8 was prepared by a method analogous to that for M6.

(±)-Ethyl 3-(2,6-difluoro-phenyl)-3-(4-hydroxy-phenyl)propanoate (M9).Compound M9 was prepared by a method analogous to that for M6.

(±)-Ethyl 3-(4-hydroxy-phenyl)-3-(5-methyl-thiophen-2-yl)propanoate(M10). Compound M10 was prepared by a method analogous to that for M6.

(±)-Oxazol-2-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol (M11.1).4-(2-Tetrahydro-3-H-pyranoxy)phenylmagnesium bromide (6.7 mmol) in THF(0.5 M) was added dropwise to a solution of oxazole-2-carbaldehyde (5.15mmol) in THF (8 mL). After it was stirred at room temperature for 2.5hours, the reaction was quenched with water and extracted with EtOAc(200 mL). The organic phase was washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was column chromatographed (silica gel, 1:2 EtOAc/hexane).Compound M11.1 was obtained. MS ESI (pos.) m/e:276 (M+H). ¹H NMR (400MHz) (DMSO-d₆) δ 8.02 (s, 1H); 7.31 (d, J=8.7 Hz, 2H); 7.14 (s, 1H);6.97-7.01 (m, 2H); 6.27 (d, J=5 Hz, 1H); 5.74 (d, J=5 Hz, 1H); 5.44 (s,1H); 3.74 (m, 1H); 3.52 (M, 1H); 1.72-1.81 (m, 3H); 1.52-1.60(m, 4H).

(±)-Oxazol-2-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (M11.2).PCC (14.5 mmol, 20% w/w on silica gel) was added to a solution of M11.1(2.91 mmol) in DCM (20 mL). After it was stirred at room temperature for1 hour, the reaction mixture was column chromatographed (silica gel, 1:2EtOAc/hexane). Compound M11.2 was obtained. MS ESI (pos.) m/e: 296.0(M+23). ¹H NMR (500 MHz) (DMSO-d₆) δ 8.52 (s, 1H); 8.43 (d, J=9 Hz, 2H);7.67 (s, 1H); 7.23 (d, J=9 Hz, 2H); 5.71 (m, 1H); 3.74-3.76 (m, 1H);3.62-3.65 (m, 1H); 1.88-1.91 (m, 2H); 1.81-1.82 (m, 1H); 1.59-1.67 (m,3H).

(E/Z)-Methyl3-(oxazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M11.3). Lithium bis(trimethylsilyl) amide (3.46 mmol, 1 M in THF) wasadded dropwise to a solution of methyl trimethylsilylacetate (3.46 mmol)in THF (5 mL) at −78° C. After it was stirred at −78° C. for 20 minutes,a solution of M11.2 (2.16 mmol) in THF (9 mL) was added dropwise, andthe temperature was maintained at −78° C. for 1.5 hours. The reactionwas quenched with water and extracted with EtOAc. The organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was columnchromatographed (silica gel, 1:1 EtOAc/hexane) and compound M11.3 wasobtained. MS ESI (pos.) m/e 330.1 (M+H).

(±)-Methyl3-(oxazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)propanoate(M11.4). A mixture of M11.3 (2.55 mmol) and Pd—C (440 mg) in MeOH wasstirred under hydrogen at room temperature for 30 minutes. The Pd—C wasremoved by filtration through silica gel eluting with EtOAc. Afterconcentration, the residue was column chromatographed (silica gel, 1:1EtOAc/hexane) and compound M11.4 was obtained. MS ESI (pos.) m/e 332.2(M+H).

(±)-Methyl 3-(4-hydroxyphenyl)-3-(oxazol-2-yl)propanoate (M11). Amixture of M11.4 (2.1 mmol), p-toluenesulfonic acid monohydrate (0.57mmol) in MeOH (15 mL) was stirred at room temperature for 1.5 hours.After it was quenched with NaHCO₃ (aqueous) solution, MeOH was removedby rotary evaporator. The residue was extracted with EtOAc, and thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, and filtered through short plug of silica gel. Afterremoving solvent, compound M11 was obtained. MS ESI (pos.) m/e 248.1(M+H). ¹H NMR (500 MHz) (DMSO-d₆) δ 9.04 (s, 1H); 7.99 (s, 1H); 7.14 (s,1H); 7.05(m, 2H); 6.72 (m, 2H); 4.49-4.52 (m, 1H); 3.57 (s, 1H);3.22-3.27(m, 1H); 2.89-2.94(m, 1H).

(1-Methyl-1H-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(M12.1). 4-(2-Tetrahydro-2H-pyranoxy)phenylmagnesium bromide (0.5 M inTHF, 160 mL, 80 mmol) was added slowly to a solution of1-methyl-2-imidazolecarboxaldehyde (8 g, 72.7 mmol) in THF (100 mL) viasyringe at −78° C. The reaction mixture was stirred at this temperaturefor 3 hours and quenched with saturated NH₄Cl (aq). The mixture wasextracted with EtOAc (2×100 mL), and the combined organic extracts weredried over Na₂SO₄, filtered, and concentrated under reduced pressure toafford M12.1 as a colorless oil (21 g), which was used directly in thenext step.

(1-Methyl-1H-imidazol-2-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(M12.2). PDC (36 g, 95.7 mmol) was added to a solution of M12.1 (21 g,72.7 mmol) in DCM (100 mL) at 0° C. in several portions. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 6 hours. Silicagel (75 g) was added to the reaction mixture, and the resulting slurrywas filtered through a pad of silica gel. The solid was washed with DCM(200 mL). The filtrate was washed with water and saturated brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give anoily residue, which was flash chromatographed (silica gel, 0-30% EtOAcin hexane) to afford ketone M12.2 as yellow solid (16 g). ¹H NMR (500MHz) (CDCl₃) δ 8.33-8.35 (m, 2H); 7.10-7.29 (m, 4H); 5.56 (t, J=3.0 Hz,1H); 4.08 (s, 3H); 3.85-3.90 (m, 1H); 3.61-3.65 (m, 1H); 2.03 (m, 1H);1.90-1.91 (m, 2H); 1.69-1.74 (m, 2H); 1.61-1.64 (m, 1H).

(Z/E)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(M12.3). A solution of lithium hexamethyldisilazide (1 M in THF, 64 mL)was added slowly to a stirred solution of ethyl (trimethylsilyl)acetate(9.9 g, 61.5 mmol) and ketone M12.2 (16 g, 55.9 mmol) in anhydrous THF(60 mL) via syringe at −78° C. The reaction mixture was stirred at thistemperature for 2 hours. The reaction temperature was allowed to rise to−20° C. over 6 hours. The reaction mixture was quenched with saturatedammonium chloride (aq) at this temperature, extracted with EtOAc (2×150mL), and dried over Na₂SO₄. After filtration, the solvent was removedunder reduced pressure to afford M12.3 as a colorless oil (21 g,including some ethyl (trimethylsilyl)acetate), which was used directlyin the next step. LC-MS ESI (pos.) m/e: 357 (M+H).

(±)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)propanoate(M12.4). A solution of olefin M12.3 (21 g, 55.9 mmol) in EtOH (200 mL)was stirred with 10% Pd—C (2.1 g, 2 mmol) under a hydrogen atmosphere(provided by a balloon) at room temperature overnight. The reactionmixture was filtered through a silica gel pad and concentrated toprovide protected ester M12.4 as an off-white oil (21 g), which was useddirectly in the next step. LC-MS ESI (pos.) m/e: 359 (M+H).

(±)-Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(M12.5). TFA (21 mL) was added to a solution of protected ester M12.4(21 g) in dry DCM (210 mL) with caution at 0° C. The mixture was broughtto room temperature over 4 hours. The reaction mixture was concentratedunder reduced pressure to provide a yellow oily residue, which wasre-dissolved in DCM (200 mL) and washed with water, saturated NaHCO₃,water and brine, and dried over Na₂SO₄. After filtration, the solventwas removed under reduced pressure, and the product was crystallized inEtOAc-hexane. The mother liquid was concentrated and flashchromatographed (silica gel, 50% EtOAc in hexane as eluant). Theproduct, (+)-ethyl3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate (M12.5) wasobtained as a colorless crystal (combined yield 11 g).

LC-MS ESI (pos.) m/e: 275 (M+H). ¹H NMR (500 MHz) (CDCl₃) δ 9.28 (s,1H); 6.98-7.00 (m, 3H); 6.65-6.77(m, 3H); 4.41 (dd, J=9.0, 3.0 Hz, 1H);3.96 (q, J=7.0, 2H); 3.39 (s, 3H); 3.19 (dd, J=16.0, 7.0 Hz, 1H); 2.78(dd, J=16.0, 6.5 Hz, 1H); 1.80 (t, J=7.0 Hz, 3H).

(S)-Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoate(M12). Racemic compound M12.5 was separated on a preparatory chiral HPLCwith CHIRALPAK AD column, using 11% i-PrOH in hexane as eluant. Eluantcontaining the peak with greater retention time was concentrated andcompound M12 was obtained as colorless crystals. The enantiomer of M12was also obtained. The absolute configuration was assigned by analogy toother GPR40 agonist compounds.

Methyl ester (M13.2). Compound M13.1 (5.5 g, 12.16 mmol, prepared asdescribed in US 2006/0004012 which is hereby incorporated by reference)was dissolved in 100 mL of EtOAc and quinoline (2 mL, 1.093 g/mL, 16.93mmol) was added. Nitrogen was bubbled through the solution for 5minutes. 500 mg of Lindlar's catalyst was added, and a hydrogen balloonwas attached. After 8 hours, the mixture was filtered through a plug ofsilica with EtOAc. The organic layer was washed with 2 N HCl (aq) (2×50mL), saturated NaHCO₃ (aq) (1×50 mL), brine (1×50 mL) and dried withMgSO₄. The organic layer was filtered and concentrated under reducedpressure. The material was chromatographed on silica with 10%EtOAc/hexane to afford M13.2 (5.1 g, 11.22 mmol) as a colorless oil. MSESI (pos.) m/e: 455.0 (M+H)⁺.

Aldehyde (M13.3). Alkene M13.2 (5.1 g, 11.22 mmol) was dissolved in 100mL of 4:1 (1,2-dioxane/water), and 2,6-lutidine (2.61 mL, 0.920 g/mL,22.44 mmol) was added. Next, 1.2 g of a 3.4% OsO₄ in t-BuOH (0.22 mmol)solution was added dropwise over 5 minutes. NaIO₄ (9.6 g, 44.88 mmol) in25 mL of water was added. The internal reaction temperature did not riseabove 30° C. After 8 hours at room temperature, the reaction mixture wasdiluted with 500 mL of DCM, the layers were separated, and the organiclayer was washed with 0.5 M HCl(aq) (2×50 mL), saturated NaHCO₃ (aq)(1×50 mL), 5% sodium sulfite (aq) (1×50 mL), and brine. The organiclayer was dried with Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was flashed on silica with 30% EtOAc/hexanes toafford M13.3 (4.0 g, 9.09 mmol) as a yellow oil. MS ESI (pos.) m/e:443.4 (M+H)⁺.

Acid (M13.4). Aldehyde M13.3 (2.32 g, 5.25 mmol) was dissolved in 20 mLof ACN. To this was added KH₂PO₄ (178 mg, 1.31 mmol) in 5 mL of water.The solution was cooled to −5° C. and 30% H₂O₂ (aq) (714 mg, 6.30 mmol)was added. NaClO₂ (712 mg, 7.88 mmol) was dissolved in 5 mL of water andadded via syringe pump over 3 hours while maintaining a temperaturebelow 0° C. After the addition of the NaClO₂ solution, the mixture wasstirred for 1 hour. 300 mL of DCM was added, and the pH of the aqueouslayer was adjusted to 2 with 2 N HCl(aq). The aqueous layer wasextracted with DCM (2×100 mL), and the combined organic extracts werewashed with 5% sodium sulfite (aq) (1×50 mL), and brine. The organiclayer was dried with NaSO₄, filtered, and concentrated under reducedpressure. The residue was chromatographed on silica with 50%EtOAc/hexanes to afford M13.4 (2.12 g, 4.62 mmol) as a colorless oil. MSESI (pos.) m/e: 459.3 (M+H)⁺.

Amide (M13.5). Acid M13.4 (6.0 g, 13.1 mmol) was dissolved in 100 mL ofDCM. To this was added 1-hydroxybenzotriazole hydrate (3.7 g, 27.5mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbondiimide hydrochloride(5.0 g, 26.2 mmol), and 2 M ammonia in n-PrOH (14 mL, 26.2 mmol). Thereaction was stirred for 8 hours and diluted with 500 mL of EtOAc. Theorganic layer was washed with 2N HCl (aq) (2×75 mL), NaHCO₃ (aq) (1×75mL), and brine (1×75 mL) and dried with MgSO₄ and filtered. The organiclayer was concentrated under reduced pressure, and the residue wasflashed through silica with 25% EtOAc/DCM. The combined fractions wereconcentrated under reduced pressure to afford M13.5 (5.3 g, 11.5 mmol)as a colorless oil.

(S)-3-(2-Methyl-2H-1,2,4-triazol-3-yl)-3-[4-(4′-trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-propionicacid (M13.6). Amide M13.5 (6.48 g, 14.2 mmol) was dissolved in 7 mL ofN,N-dimethylformamide dimethyl acetal (119.17 MW, 0.894 g/mL, 52.6mmol). The solution was gradually heated to 80° C. over 30 minutes. Themixture was allowed to cool to 35° C., and the sample was concentratedunder reduced pressure. The residue was dissolved in 20 mL of AcOHfollowed by careful addition of methylhydrazine (5 mL, 0.866 g/mL, 94.0mmol) over 5 minutes (the acid/base exotherm was used to run thereaction). The temperature increased to 65° C., and an oil bath at 80°C. was used to finish the reaction. The total heating time was 45minutes. The reaction was allowed to come to room temperature, and wasdiluted with 500 mL of DCM. The organic layer was washed with water(3×100 mL), brine (1×100 mL), dried with Na₂SO₄, filtered, andconcentrated to a residue. The material was flashed on silica with 10%ACN/DCM to afford methyltriazole M13.6 (4.3 g, 8.7 mmol) as a yellowoil. MS ESI (pos.) m/e: 496.5 (M+H)⁺.

(S)-Methyl3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate (M13).Methyltriazole M13.6 (2.78 g, 5.61 mmol) was dissolved in 50 mL ofEtOAc, and nitrogen was bubbled through the solution for 5 minutes. 1 gof palladium on carbon (5 wt. %, wet contains 50% water) was added, anda hydrogen balloon was attached. After 8 hours, the mixture was filteredthrough a plug of silica with 10% MeOH in EtOAc. The organic layer wasconcentrated under reduced pressure and partitioned between ACN (100 mL)and hexane (50 mL). The ACN layer was washed with hexane (4×50 mL). TheACN layer was concentrated under reduced pressure to afford (S)-methyl3-(4-hydroxyphenyl)-3-(2-methyl-2H-1,2,4-triazol-3-yl)propanoate M13(1.30 g, 4.99 mmol) as a colorless oil. MS ESI (pos.) m/e: 262.4 (M+H)⁺.6.14 Method 14

Methylamide (M14.1). Acid M13.4 (6.0 g, 13.1 mmol), prepared asdescribed above, was dissolved in 100 mL of DCM. To this mixture wasadded 1-hydroxybenzotriazole hydrate (3.7 g, 27.5 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbondiimide hydrochloride (5.0 g,26.2 mmol), and 2 M methylamine in THF (14 mL, 26.2 mmol). The reactionwas stirred for 8 hours, diluted with 500 mL of EtOAc, and the organiclayer was washed with 2N HCl(aq) (2×75 mL), NaHCO₃ (aq) (1×75 mL), brine(1×75 mL) and dried with MgSO₄ and filtered. The organic layer wasconcentrated under reduced pressure, and the residue was flashed throughsilica with 15% EtOAc/DCM. The combined fractions were concentratedunder reduced pressure to afford M14.1 (4.2 g, 11.5 mmol) as a colorlessoil. MS ESI (pos.) m/e: 472.3 (M+H)⁺.

(S)-3-(1-Methyl-1H-tetrazol-5-yl)-3-[4-(4′-trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-propionicacid (M14.2). Methylamide M14.1 (2.15 g, 4.59 mmol) was dissolved in 50mL of ACN. NaN₃ (900 mg, 13.8 mmol) was added followed by the dropwiseaddition of Tf₂O (5.2 g, 18.4 mmol). The temperature rose to 34° C. Thereaction was stirred for 12 hours and diluted with 250 mL of DCM. Theorganic layer was washed with NaHCO₃ (aq) (2×50 mL), brine (1×50 mL) anddried with MgSO₄ and filtered. The organic layer was concentrated underreduced pressure, and the residue was flashed through silica with 15%EtOAc/DCM. The combined fractions were concentrated under reducedpressure to afford methyltetrazole M14.2 (1.52 g, 3.07 mmol) as acolorless oil. MS ESI (pos.) m/e: 497.4 (M+H)⁺.

(S)-Methyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-tetrazol-5-yl)propanoate(M14). Methyltetrazole M14.2 (413 mg, 0.833 mmol) was dissolved in 5 mLof EtOAc and nitrogen was bubbled through the solution for 5 minutes.Palladium on carbon (200 mg, 5 wt. %, wet contains 50% water) was added,and a hydrogen balloon was attached. After 8 hours, the mixture wasfiltered through a plug of silica with 10% MeOH in EtOAc. The organiclayer was concentrated under reduced pressure and partitioned betweenACN (10 mL) and hexane (5 mL). The ACN layer was washed with hexane (4×5mL). The ACN layer was concentrated under reduced pressure to afford(S)-methyl 3-(4-hydroxyphenyl)-3 -(1-methyl-1H-tetrazol-5-yl)propanoate(M 14) (203 mg, 0.775 mmol) as a colorless oil.6.15 Method 15

2,2-Dimethyl-5-(3-methyl-1-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)but-2-enyl)-1,3-dioxane-4,6-dione(M 15.1). To a solution of M1.1 (50 g, 0.15 mol) in THF (300 mL) at 0°C. was cannulated 2-methyl-1-propenyl magnesium bromide (600 mL, 0.5 Min THF, 0.30 mol) during a 1 hour period. The reaction was left at roomtemperature for 2 hours and then was quenched with water, extracted withethyl acetate, and dried with MgSO₄. The solvent was removed to afford agel-like M 15.1, which was used as such in the next step.

Ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate (M15.2). A solution ofM15.1 in EtOH:pyridine (200 mL, 9:1 v/v) was heated to 120° C.overnight. After cooling, the reaction was acidified with 2 N HCl aq.,and extracted with ethyl acetate. The organic layer was dried overMgSO₄, filtered, and concentrated to afford M15.2. MS ESI (pos.) m/e:249.1 (M+H).

(S)-Ethyl 3-(4-hydroxyphenyl)-5-methylhex-4-enoate (M15.3) and (R)-ethyl3-(4-hydroxyphenyl)-5-methylhex-4-enoate (M15.4). Racemic compound M15.2was separated on a preparatory chiral HPLC. M15.3, and M15.4 wereassigned arbitrarily.

6.16 Example 1

(±)-5-Bromo-2,3-dihydro-1H-inden-1-ol (1.1). To a clear solution of5-bromo-1-indanone (1.0 g, 4.7 mmol) in MeOH (6 mL) was added NaBH₄(0.36 g, 9.5 mmol). The mixture was stirred at room temperatureovernight. The mixture was concentrated to dryness and redissolved inwater/EtOAc. The layers were separated and the EtOAc layer was driedwith anhydrous Na₂SO₄ and concentrated to obtain 1.1, which was useddirectly in the next step. ¹HNMR (DMSO-d₆) δ 7.41 (s, 1H), 7.36 (d, 1H,J2=8.08 Hz), 7.26 (d, 1H, J1=7.99 Hz), 5.28 (d, 1H, J=5.90 Hz), 4.99 (q,1H), 2.91 (m, 1H), 2.71 (m, 1H), 2.33 (m, 1H), 1.78 (m, 1H).

(±)-5-Bromo-1-chloro-2,3-dihydro-1H-indene (1.2). A solution of 1.1 (2.0g) in DCM (10 mL) in an ice-bath, was treated with thionyl chloride (10mL). The reaction mixture was stirred at room temperature for 2 hours.The reaction mixture was then poured into ice water and extracted withEtOAc. The organic layer was dried (MgSO₄), filtered, and concentratedunder vacuum. The resulting material was chromatographed on a silica gelcolumn, eluting with 5-10% EtOAc in hexane, to afford 1.2. ¹H NMR(DMSO-d₆) δ 7.54 (s, 1H), 7.45 (dd, 1H, J1=1.0 Hz, J2=8.50 Hz), 7.37 (d,1H, J=8.0 Hz), 3.07 (m, 1H), 5.60 (q, 1H), 2.93 (m, 1H), 2.59(m, 1H),2.26 (m, 1H).

(3S)-Methyl3-(4-(4-bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoate (1.3). Amixture of (S)-methyl 3-(4-hydroxyphenyl)hex-4-ynoate (1, 0.65 g, 2.9mmol), Cs₂CO₃ (1.40 g, 4.3 mmol), and 1.2 (1.0 g, 4.3 mmol) in DMF (5mL), was heated to 80° C. for 8 hours. The reaction mixture wasconcentrated, and the residue was chromatographed on a silica gelcolumn, eluting with 5-10% EtOAc in hexane, providing 1.3. MS ESI (pos.)m/e: 413.0 (M+H).

6.16.1 General Procedure A: Suzuki Coupling

(3S)-Methyl3-(4-(5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoate(1.4). A mixture of 1.3 (74 mg, 0.18 mmol),4-(trifluoromethyl)phenylboronic acid (45.8 mg, 0.22 mmol) and CsF (56mg, 0.37 mmol) in 1,2-dimethoxyethane (2 mL), was degassed with N₂ for 3minutes. Pd(PPh₃)₄ (21 mg, 0.018 mmol) was added, and the resultingmixture was heated at 95° C. for 8 hours. After cooling, the reactionmixture was quenched with water and extracted with EtOAc providing 1.4(20 mg), which was directly hydrolyzed in the next step.

6.16.2 General Procedure B: Alkaline Hydrolysis

(3S)-3-(4-(5-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (1.5). A solution of 1.4 (20 mg) in THF/MeOH (1:1, 6 mL), wastreated with 30% aqueous NaOH solution (3 mL) and stirred for 2 hours atroom temperature. The reaction mixture was acidified with aqueous 2N HCland extracted with EtOAc providing 1.5, which was chromatographed on asilica gel column, eluting with 20˜40% EtOAc in hexane. MS ESI (neg.)m/e: 463.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.24 (br, 1H), 7.91 (d, 2H, J=8.22Hz), 7.83 (d, 2H, J=8.35 Hz), 7.70 (s, 1H), 7.61 (d, 1H, J=7.84 Hz),7.51 (d, 1H, J=7.92 Hz), 7.32 (d, 2H, J=8.67 Hz), 7.02 (d, 2H, J=8.68Hz), 5.99 (m, 1H), 3.99 (m, 1H), 3.11 (m, 1H), 3.00 (m, 1H), 2.59-2.64(m, 3H, CH2, CH), 2.09 (m, 1H), 1.81 (ss, 3H), 1.80.

6.17 Example 2

(3S)-3-[4-(5-Bromo-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (2). Compound2 was obtained from compound 1.3 by following general procedure B ofExample 1. MS ESI (neg.) M/E: 397.0, 399.1 (M−H). ¹HNMR (DMSO-d₆) δ12.25 (br, 1H), 7.55 (s, 1H), 7.43 (dd, 1H, J1=1.77 Hz, J2=8.05 Hz),7.20-7.38 (m, 3H), 7.00 (d, 2H, J=8.68 Hz), 5.79 (m, 1H), 3.96 (m, 1H),3.07 (m, 1H), 2.92 (m, 1H), 2.62 (d, 2H, J=7.49 Hz), 2.57 (m, 1H), 2.05(m, 1H), 1.81, 1.80 (ss, 3H).

6.18 Example 3

(3S)-3-(4-(5-(2-Butoxy-5-methylphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (3). This compound was obtained from compound 1.3 by followinggeneral procedures A and B of Example 1. MS ESI (neg.) ESI (neg.) m/e:481.3 (M−H). ¹HNMR (DMSO-d₆), δ 12.22 (br, 1H), 7.24-7.42 (m, 6H), 7.11(m, 2H), 6.99 (m, 3H), 5.76(m, 1H), 4.03(m, 1H), 3.96 (t, 2H, J=6.37Hz), 3.05 (m, 1H), 2.91 (m, 1H), 2.55-2.68 (m, 3H, CH2, CH), 2.34 (s,3H), 2.06 (m, 1H), 1.92 (s, 3H), 1.60 (m, 2H), 1.41 (m, 2H), 0.89 (t,3H, J=7.32 Hz).

6.19 Example 4

(3S)-3-[4-(5-Thiophen-2-yl-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (4).Compound 4 was prepared by a method analogous to that for 1.3. MS ESI(neg.) m/e: 401.2 (M−H). ¹HNMR (DMSO-d₆) δ 12.27 (br, 1H), 7.62 (s, 1H),7.52-7.56 (m, 3H), 7.41 (d, 1H, J=7.87 Hz), 7.31 (d, 2H, J=8.47 Hz),7.16 (t, 1H, J=4.99 Hz), 7.00 (d, 2H, J=8.49), 5.84(m, 1H), 3.98 (m,1H), 3.05 (m, 1H), 2.91 (m, 1H), 2.64 (d, 2H, J=7.52 Hz), 2.58 (m, 1H),2.07 (m, 1H), 1.81, 1.80 (ss, 3H).

6.20 Example 5

(3S)-3-[4-(4-Bromo-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (5). Thiscompound was prepared by a method analogous to that for 2. MS ESI (neg.)m/e: 399.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.23 (br, 1H), 7.56 (d, 1H, J=7.65Hz), 7.41 (d, 1H, J=7.34 Hz), 7.32 (d, 2H, J=8.41 Hz), 7.07 (t, 1H,J=7.63 Hz), 7.00 (d, 2H, J=8.33 Hz), 3.97 (m, 1H), 5.92 (m, 1H), 3.12(m, 1H), 2.88 (m, 1H), 2.62 (m, 3H, CH2, CH), 2.06 (m, 1H), 1.80 (s,3H).

6.21 Example 6

(3S)-3-{4-[4-(4-Trifluoromethoxy-phenyl)-indan-1-yloxy]-phenyl}-hex-4-ynoicacid (6). Compound 6 was prepared by a method analogous to that for 1.5.MS ESI (neg.) m/e: 479.2 (M−H). ¹HNMR (DMSO-d₆) δ 12.21 (br, 1H), 7.66(d, 2H, J=8.40 Hz), 7.31-7.48 (m, 7H), 7.03 (d, 2H, J=8.40 Hz), (m, 1H),3.97 (m, 1H), 3.09 (m, 1H), 2.95 (m, 1H), 2.64 (m, 3H, CH2, CH), 2.01(m, 1H), 1.81 (s, 3H).

6.22 Example 7

(3S)-3-{4-[4-(4-Trifluoromethoxy-phenyl)-indan-1-yloxy]-phenyl}-hex-4-ynoicacid (7). Compound 7 was prepared by a method analogous to that for 1.5.MS ESI (neg.) m/e: 463.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.25 (br, 1H), 7.84(d, 2H, J=8.25 Hz), 7.76 (d, 2H, J=8.16 Hz), 7.41-7.49 (m, 3H), 7.32 (d,2H, J=8.57 Hz), 7.03 (d, 2H, J=8.59 Hz), 5.89 (t, 1H, J=4.99 Hz), 3.98(m, 1H), 3.09 (m, 1H), 2.96 (m, 1H), 2.68 (d, 2H, J=7.60 Hz), 2.60 (m,1H), 2.05 (m, 1H), 1.81, 1.80, (ss, 3H).

6.23 Example 8

(3S)-3-{4-[4-(2-Butoxy-5-methyl-phenyl)-indan-1-yloxy]-phenyl}-hex-4-ynoicacid (8). Compound 8 was prepared by a method analogous to that for 1.5.MS ESI (neg.) M/E: 481.3 (M−H).

6.24 Example 9

(3S)-3-{4-[4-(3-Ethoxy-phenyl)-indan-1-yloxy]-phenyl}-hex-4-ynoic acid(9). Compound 9 was prepared by a method analogous to that for 1.5. MSESI (neg.) m/e: 439.1 (M−H).

6.25 Example 10

(3S)-3-[4-(4-Bromo-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (10).Compound 10 was prepared by a method analogous to that for 2. MS ESI(neg.) m/e: 399.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.25 (br, 1H), 7.49-7.54 (m,2H), 7.30 (m, 3H), 7.00 (d, 2H, J=8.60 Hz), 5.82 (t, 1H, J=5.84 Hz),3.96 (m, 1H), 3.00 (m, 1H), 2.86 (m, 1H), 2.63 (d, 2H, J=7.56 Hz), 2.57(m, 1H), 2.05 (m, 1H), 1.81, 1.80 (ss, 3H).

6.26 Example 11

(3S)-3-(4-(6-(4-(trifluoromethyl)phenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (11). Compound 11 was prepared by a procedure analogous to thatdescribed for 1.5. MS ESI (neg.) m/e: 463.1 (M−H). ¹HNMR (DMSO-d₆) δ12.21 (br, 1H), 7.87 (d, 2H, J=8.18 Hz), 7.80 (d, 2H, J=8.37 Hz),7.69-7.72 (m, 2H), 7.48 (d, 1H, J=7.84 Hz), 7.32 (d, 2H, J=8.65 Hz),7.03 (d, 2H, J=8.62 Hz), 5.89 (m, 1H), 3.99 (m, 1H), 3.10 (m, 1H), 2.96(m, 1H), 2.60-2.65 (m, 3H, CH2, CH), 2.09 (m, 1H), 1.81, 1.80 (ss, 3H).

6.27 Example 12

(3S)-3-{4-[6-(2-Butoxy-5-methyl-phenyl)-indan-1-yloxy]-phenyl)-hex-4-ynoicacid (12). Compound 12 was prepared by a procedure analogous to thatdescribed for 1.5. MS ESI (neg.) m/e: 481.3 (M−H). ¹HNMR (DMSO-d₆) δ12.20 (br, 1H), 7.50 (s, 1H), 7.41 (d, 1H, J=7.60 Hz), 7.33 (d, 1H,J=6.00 Hz), 7.29 (d, 2H, J=6.80 Hz), 7.08 (m, 2H), 6.98 (m, 3H), 5.83(t, 1H, J=5.20 Hz), 3.96 (m, 1H), 3.90 (t, 2H, J=5.20 Hz), 3.40 (m, 1H),2.92 (m, 1H), 2.61 (d, 2H, J=8.50 Hz), 2.26(s, 3H), 2.05 (m, 1H), 1.79,1.78 (ss, 3H), 1.57 (m, 2H), 1.36 (m, 2H), 0.85 (t, 3H, J=5.60 Hz).

6.28 Example 13

(3S)-3-{4-[6-(4-Trifluoromethoxy-phenyl)-indan-1-yloxy]-phenyl}-hex-4-ynoicacid (13). Compound 13 was prepared by a procedure analogous to thatdescribed for 1.5. MS ESI (neg.) m/e: 479.2 (M−H). ¹HNMR (DMSO-d₆) δ12.21 (br, 1H), 7.77 (m, 2H), 7.63 (s, 1H), 7.45-7.56 (m, 4H), 7.32 (d,2H, J=8.69 Hz), 7.02 (d, 2H, J=8.69 Hz), 5.88 (m, 1H), 3.98 (m, 1H),3.12 (m, 1H), 2.94 (m, 1H), 2.63 (d, 2H, J=7.69 Hz), 2.57 (m, 1H), 2.09(m, 1H), 1.81, 1.80 (ss, 3H).

6.29 Example 14

(3S)-3-(4-(5-Fluoro-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoic acid(14). To a mixture of compound 1 (100 mg, 0.46 mmol), 4-fluoroindan-1-ol(65 mg, 0.42 mmol), and tributylphosphine (0.17 mL, 0.84 mmol) in THF (3mL) was added N,N,N′,N′-tetramethylazodicarboxamide(TMAD) (0.15 g, 0.87mmol). The reaction mixture was stirred at room temperature overnight.The reaction mixture was quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column to afford the ester. The esterwas hydrolyzed to provide compound 14 using general procedure B (seeConversion of 1.4 to 1.5). MS ESI (neg.) m/e: 337.1 (M−H). ¹HNMR(DMSO-d₆) δ 12.25 (br, 1H), 7.41 (m 1H), 7.30 (d, 2H, J=8.40 Hz), 7.17(dd, 1H, J1=9.20 Hz, J2=1.6 Hz), 7.07 (td, 1H, J1=9.2 Hz, J2=2.40 Hz),6.98 (d, 2H, J=8.40 Hz), 5.78 (m, 1H), 3.99 (m, 1H), 3.05 (m, 1H), 2.88(m, 1H), 2.62 (d, 2H, J=7.60 Hz), 2.55 (m, 1H), 2.04 (m, 1H), 1.81, 1.80(ss, 3H).

6.30 Example 15

(3S)-3-[4-(5-Chloro-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (15).Compound 15 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 353.2 (M−H). ¹HNMR (DMSO-d₆) δ 12.25 (br, 1H),7.41 (m, 2H), 7.29 (m, 3H), 6.99 (d, 2H, J=8.63 Hz), 5.81 (m, 1H), 3.98(m, 1H), 3.02 (m, 1H), 2.90 (m, 1H), 2.55-2.64 (m, 3H), 2.06 (m, 1H),1.81, 1.80 (s, 3H).

6.31 Example 16

(3S) 3-[4-(4-Methyl-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (16).Compound 16 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 333.3 (M−H). ¹HNMR (DMSO-d₆) δ 12.26 (br, 1H),7.30 (d, 2H, J=8.66 Hz), 7.19-7.28 (m, 1H), 7.12-7.15 (m, 2H), 6.98 (d,2H, J=8.66 Hz), 5.81 (m, 1H), 3.97 (m, 1H), 2.94 (m, 1H), 2.82 (m, 1H),2.62 (d, 2H, J=7.61 Hz), 2.56 (m, 1H), 2.27 (s, 3H), 2.04 (m, 1H), 1.81,1.80(ss, 3H).

6.32 Example 17

(3S)-3-[4-(6-Methoxy-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (17).Compound 17 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 349.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.25 (br, 1H),7.29 (d, 2H, J=8.50 Hz), 7.21 (d, 1H, J=8.50 Hz), 6.98 (d, 2H, J=9.00Hz), 6.88-6.91 (m, 2H), 5.76 (m, 1H), 3.97 (m, 1H), 3.72 (s, 3H), 2.95(m, 1H), 2.60 (d, 2H, J=7.50 Hz), 2.79 (m, 1H), 2.54 (m, 1H), 2.01 (m,1H), 1.80, 1.79 (ss, 3H).

6.33 Example 18

(3S)-3-[4-(5-Methoxy-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (18).Compound 18 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 349.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.24 (br, 1H),7.25-7.30 (m, 3H), 6.96 (d, 2H, J=8.66 Hz), 6.90(m, 1H), 6.80 (dd, 1H,J1=2.40 Hz, J2=8.34 Hz), 5.75 (m, 1H), 3.97 (m, 1H), 3.76 (s, 3H), 3.00(m, 1H), 2.87 (m, 1H), 2.59 (d, 2H, J=7.66 Hz), 2.54 (m, 1H), 2.04 (m,1H), 1.80 1.79 (ss, 3H).

6.34 Example 19

(3S)-3-[4-(4,5-Dimethoxy-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (19).Compound 19 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 379.1 (M−H).

6.35 Example 20

(3S)-3-[4-(4,7-Dimethoxy-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (20).Compound 20 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 379.1 (M−H). ¹HNMR (DMSO-d₆) δ 12.26 (br, 1H),7.28 (d, 2H, J=8.44 Hz), 6.91 (m, 3H), 6.80 (d, 1H, J=8.68 Hz), 5.80 (d,1H, J=5.98 Hz), 3.96 (m, 1H), 3.77 (s, 3H), 3.70 (s, 3H), 2.92 (m, 1H),2.79 (m, 1H), 2.62 (d, 2H, J=7.40 Hz), 2.37 (m, 1H), 2.08 (m, 1H), 1.79(s, 3H).

6.36 Example 21

(3S)-3-[4-(2-Methyl-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (21).Compound 21 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 333.3 (M−H). ¹HNMR (DMSO-d₆) δ 12.27 (br, 1H),7.28-7.35 (m, 5H), 7.19-7.23 (m, 1H), 7.04 (d, 1H, J=8.61 Hz), 7.00 (d,1H, J=8.59Hz), 5.73 (ss, 0.5H), 5.41 (ss, 0.5H), 3.98 (m, 1H), 3.20 (m,0.5H), 3.06 (m, 0.5H), 2.88 (m, 0.5H), 2.70 (m, 0.5H), 2.64 (d, 2H,J=4.93 Hz), 1.80 (s, 3H), 1.16 (ss 1.5H), 0.96(s, 1.5H).

6.37 Example 22

(3S)-3-[4-(2-Methyl-indan-1-yloxy)-phenyl]-hex-4-ynoic acid (22).Compound 22 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 344.2 (M−H). ¹HNMR (DMSO-d₆) δ 12.25 (br, 1H),7.81 (s, 1H), 7.70 (d, 1H, J=8.00 Hz), 7.56 (d, 1H, J=8.00 Hz), 7.03 (d,2H, J=8.50 Hz), 7.00 (d, 2H, J=8.50 Hz), 5.89 (t, 1H, J=5.50 Hz), 3.96(m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 2.62 (d, 2H, J=4.50 Hz), 2.04 (m1H), 1.79, 1.78 (ss, 3H).

6.38 Example 23

(±)-3-(4-(5-Chloro-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(5-methylthiophen-2-yl)propanoicacid (23). Compound 23 was prepared from compound M10 by a procedureanalogous to that described for 14. MS ESI (neg.) m/e: 411.1 (M−H).¹HNMR (DMSO-d₆) δ 12.19 (br, 1H), 7.37-7.40 (m, 2H), 7.27-7.29 (m, 1H),7.22 (d, 2H, J=8.50 Hz), 6.95(d, 2H, J=8.50 Hz), 6.71 (d, 1H, J=3.0 Hz),6.59 (dd, 1H, J1=1.0 Hz, J2=3.0 Hz), 5.76-5.79 (m, 1H), 4.49 (t, 1H,J=7.50 Hz), 2.96-3.06 (m, 2H), 2.86-2.91 (m, 2H), 2.54-2.59 (m, 1H),2.34 (s, 3H), 1.99-2.04 (m, 1H).

6.39 Example 24

(3S)-3-[4-(1,2,3,4-Tetrahydro-naphthalen-1-yloxy)-phenyl]-hex-4-ynoicacid (24). Compound 24 was prepared from compound M1 by a procedureanalogous to that described for 14, except that LiOH was used forhydrolysis, instead of NaOH. MS ESI (neg.) m/e: 333 (M−H). ¹HNMR (CDCl₃)δ 7.4(m, 3H), 7.2 (m, 2H), 7.0 (d, 2H), 5.4 (s, 1H), 4.05(br s, 1H),3.0-2.7 (m, 4H), 2.2-2.0 (m, 3H), 1.85 (s, 3H), 1.8 (m, 1H).

6.40 Example 25

(3S)-3-[4-(5-Bromo-1,2,3,4-tetrahydro-naphthalen-1-yloxy)-phenyl]-hex-4-ynoicacid (25). Compound 25 was prepared from compound M1 by a procedureanalogous to that described for 14, except that LiOH was used forhydrolysis, instead of NaOH. MS ESI (neg.) m/e: 413 (M−H). ¹HNMR (CDCl₃)δ 7.55(m, 1H), 7.35 (m, 3H), 7.1 (m, 1H), 6.95(d, 2H), 5.35 (s, 1H),4.05(br s, 1H), 3.0-2.8 (m, 4H), 2.1-1.95 (m, 3H), 1.85 (br s, 4H).

6.41 Example 26

(3S)-3-[4-(1,2,3,4-Tetrahydro-naphthalen-2-yloxy)-phenyl]-hex-4-ynoicacid (26). A solution of compound M1 (100 mg, 0.46 mmol),1,2,3,4-tetrahydro-naphthalen-2-ol (102 mg, 0.69 mmol) in toluene (2 mL)was treated with a solution of cyanomethylenetributylphophorane (166 mg,0.69 mmol) in toluene (2 mL). The reaction mixture was stirred at 70° C.for 18 hours. The reaction mixture was directly chromatographed on asilica gel column eluting with 5-25% EtOAc in hexane. The ester obtained(36 mg) was hydrolyzed to give 26 using general procedure B (Seeconversion of 1.4 to 1.5) above except that LiOH was used for hydrolysisinstead of NaOH. MS ESI (neg.) m/e: 333 (M−H). ¹HNMR (CDCl₃) δ 7.25(d,2H), 7.15 (m, 4H), 6.9(d, 2H), 4.7 (s, 1H), 4.1(s, 1H), 3.2 ( dd, 1H),3.05(m, 2H), 2.9-2.7 (m, 3H), 2.2 (m, 1H), 2.0(m, 1H), 1.85 (s, 3H).

6.42 Example 27

(3S)-3-14-(Indan-2-yloxy)-phenyl]-hex-4-ynoic acid (27). A pear shapedflask was charged with a stir bar, phenol M1 (150 mg, 0.65 mmol),triphenylphosphine (204 mg, 0.78 mmol), 2-indanol (104 mg, 0.78 mmol),and DCM (5 mL). To the resulting solution, DIAD (158 mg, 154 μL, 0.78mmol) was added drop-wise via syringe. The resulting solution wasstirred at room temperature overnight. The reaction was filtered througha Hirsch funnel to remove precipitates, and radially chromatographed(4:1 hexane: EtOAc) to yield ester 27.1. MS ESI (pos.) m/e: 335.2 (M+H).

To a solution of ester (79 mg, 0.23 mmol) in EtOH (2 mL), was added 2NNaOH (2 mL, 4.0 mmol). The resulting solution was stirred at roomtemperature overnight. The solvent was removed in vacuo, and theresulting residue was partitioned between 1N HCl and EtOAc. The solutionwas extracted one additional time with EtOAc. The combined organiclayers were concentrated, and the resulting residue was radiallychromatographed (3:2 hexane:ethylacetate+0.1% AcOH) to yield 27. MS ESI(pos.) m/e: 321.1 (M+H). ¹H NMR (400 MHz) (CHCl₃-d₃) δ 7.31-7.19 (m,6H); 6.86 (d, 2H, J=8 Hz); 4.15-4.06 (m, 2H); 3.36 (m, 2H); 3.17 (d, 2H,J=16 Hz); 2.56 (m, 2H); 1.84 (s, 3H).

6.43 Example 28

(±)-Methyl 3-(4-(4-phenylcyclohexyloxy)phenyl)hex-4-ynoate (28). Apear-shaped flask (25 mL) was equipped with a magnetic stir bar, anitrogen inlet and a nitrogen outlet. The compound (±)-M1 (0.05 g, 0.229mmol) was added to the flask and dissolved in 0.6 mL of anhydroustoluene. To this solution, 4-phenylcyclohexanol (0.061 g, 0.344 mmol)and triphenylphosphine (0.078 g, 0.298 mmol) were added. DIAD (0.07 g,0.344 mmol) was added, and the reaction was allowed to stir at roomtemperature. When the reaction was complete, the solution wasconcentrated in vacuo and the residue was dissolved in a minimal amountof DCM. The solution was flash column chromatographed with 0 to 100%EtOAc/hexanes as the eluant. The fractions were combined andconcentrated to afford 28 as a viscous oil.

6.44 Example 29

(R, S)-3-(4-(4-phenylcyclohexyloxy)phenyl)hex-4-ynoic acid (29).Compound 28 (0.05 g, 0.133 mmol) was added to a 3-dram vial anddissolved in a minimal amount of anhydrous THF. An aqueous solution oflithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was addeddropwise until the layers were miscible. The vial was sealed and placedon a rotating wheel overnight (18 hours). When the reaction wascomplete, the solvent was concentrated under a flow of nitrogen untilonly water was left. The mixture was diluted by the addition of ˜1 mL ofwater. Hydrochloric acid (3 N aqueous solution) was added dropwise untilthe pH reached 2. The aqueous solution was extracted with DCM, and theorganic layer was dried and concentrated. HPLC of the residue afforded29 as a white film. MS ESI (pos.) m/e: 363.2 (M+H). ¹H NMR (400 MHz)(CDCl₃) δ 7.35-7.22 (m, 7H); 6.93 (m, 2H); 4.62 (m, 1H); 4.08 (m, 1H);2.84 (dd, J=15.6, 8.5 Hz, 1H); 2.74 (dd, J=15.6, 6.6 Hz, 1H); 2.66-2.58(m, 1H); 2.21-2.18 (m, 2H); 1.99-1.91 (m, 2H); 1.86 (d, J=2.41 Hz, 3H);1.73-1.61 (m, 4H).

6.45 Example 30

(±)-Methyl3-(4-(4-phenylcyclohexyloxy)phenyl)-3-(thiophen-2-yl)propanoate (30).Compound M4 (0.2 g, 0.76 mmol) was added to a 3-dram vial and dissolvedin 0.25 mL of anhydrous THF. To this solution, 4-phenylcyclohexanol(0.148 g, 0.84 mmol) and triphenylphosphine (0.22 g, 0.84 mmol) wereadded. The vial was sealed and submerged in a sonicator for 3 minutes tomix the solution. DIAD (0.17 g, 0.84 mmol) was added over 2 minutes.After the addition was complete, the vial was sealed and again partiallysubmerged in the sonicator for 15 minutes. After sonication wascomplete, the solution was concentrated in vacuo, and the residue wasdissolved in a minimal amount of DCM. The solution was loaded onto a 12g REDISEP® column and flash chromatographed with 0 to 100% EtOAc/hexanesas the eluant. The fractions were combined and concentrated to afford 30as a viscous oil.

6.46 Example 31

(±)-3-(4-(4-Phenylcyclohexyloxy)phenyl)-3-(thiophen-2-yl)propanoic acid(31). Compound 30 (0.048 g, 0.11 mmol) was added to a 1-dram vial anddissolved in a minimal amount of anhydrous THF. An aqueous solution oflithium hydroxide (2 M, 0.3 mL) was added to the vial. MeOH was addeddropwise until the layers were miscible. The vial was sealed and placedon a rotating wheel overnight (18 hours). When the reaction wascomplete, the solvent was concentrated under a flow of nitrogen untilonly water was left. The mixture was diluted by the addition of ˜1 mL ofwater. Hydrochloric acid (3 N aqueous solution) was added dropwise untilthe pH reached 2. The aqueous solution was extracted with DCM, and theorganic layer was dried and concentrated. Flash column chromatographywith 0 to 100% EtOAc/hexanes as the eluant and HPLC of the residueafforded 31 as a white film. MS ESI (pos.) m/e: 407.2 (M+H). ¹H NMR (400MHz) (CDCl₃) δ 7.35-7.2 (m, 7H); 7.17 (dd, J=5.1, 1.0 Hz, 1H); 6.93-6.73(m, 4H); 4.72 (m, 1H); 4.61 (m, 1H); 3.16 (dd, J=15.9, 7.6 Hz, 1H); 3.07(dd, J=15.9, 7.9); 2.61 (m, 1H); 2.19 (m, 2H); 2.02-1.95 (m, 2H);1.73-1.61 (m, 4H); 0.91-0.69 (m, 2H).

6.47 Example 32

(±)-3-(4-(2,3-Dihydro-1H-inden-2-yloxy)phenyl)3-(oxazol-2-yl)propanoicacid (32). Compound 32 was made by a procedure similar to that used forthe synthesis of 30 and 31 using M11 and the appropriate alcohol. MS ESI(neg.) m/e: 348 (M−H). ¹H NMR (500 MHz) (CD₃OD) δ 7.84 (1H, d, J=0.5Hz); 7.24-7.26 (4H, m); 7.18 (2H, m); 7.14 (1H, m); 6.92 (2H, m);5.23(1H, m); 4.64 (1H, m); 3.40 (2H, m); 3.31 (1H, m); 3.13 (1H, m);3.09 (1H, m); 2.95-2.98 (1H, m).

6.48 Example 33

(±)-3-(4-(5-Chloro-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(oxazol-2-yl)propanoicacid (33). Compound 33 was made by a procedure similar to one used forthe synthesis of compounds 30 and 31 using M11 and the appropriatealcohol. MS ESI (neg.) m/e: 382 (M−H). ¹H NMR (500 MHz) (CD₃OD) 8 7.85(1H, s); 7.36 (2H, m); ); 7.25 (3H, m); 7.14 (1H, s); 7.00 (2H, m); 5.80(1H, m); 4.65 (1H, m); 3.32 (1H, m); 3.15 (1H, m); 2.54 (1H, m); 2.62(1H, m); 2.17 (1H, m).

6.49 Example 34

(±)-3-(4-(5-Chloro-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoicacid (34). Compound 45 was made by a procedure similar to one used forthe synthesis of 30 and 31 using M5 and the appropriate alcohol. MS ESI(neg.) m/e: 396 (M−H). ¹H NMR (500 MHz) (DMSO-d6) δ 12.3 (1H, s); 7.42(2H, d, J=8 Hz); 7.31 (1H, d, J=8.5 Hz); 7.21 (2H, d, J=8.5 Hz); 7.01(2H, d, J=8.5 Hz); 6.76 (1H, m); 4.80 (1H, s); 4.45 (1H, m); 3.13 (1H,m); 2.90 (1H, m); 2.81 (1H, m); 2.60 (1H, m); 2.53 (3H, s).

6.50 Example 35

(±)Ethyl3-(3,5-difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoate(35). At room temperature,3-(4-fluoro-phenyl)-3-(4-hydroxy-phenyl)-propionic acid ethyl ester M6(0.2 mmol ) and 2-indanyl p-toluenesulphonate (0.3 mmol) were dissolvedin 2 mL dry DMF, and Cs₂CO₃ (0.3 mmol) was added to the above solution.The mixture was diluted with 50 mL EtOAc after being stirred at roomtemperature for 3 days. The mixture was washed with water twice (30mL×2) and dried over Na₂SO₄. The solid was filtered, solvent wasevaporated, and the residue oil was chromatographed on a silica gelcolumn. (±)3-(4-Fluoro-phenyl)-3-[4-(indan-2-yloxy)-phenyl]-propionicacid ethyl ester 35 was obtained as colorless oil. MS ESI (pos.) m/e:405 (M+H).

6.51 Example 36

(±)3-(3,5-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoicacid (36).(±)3-(3,5-Difluoro-phenyl)-3-[4-(indan-2-yloxy)-phenyl]-propionic acidethyl ester 35 (25 mg) was dissolved in 3 mL THF-EtOH-H₂O (1/1/1), andLiOH (20 mg) was added. The mixture was stirred at room temperature for6 hours. 1N HCl was added to acidify the mixture to pH 2-3. The mixturewas extracted with EtOAc (2×20 mL). The organic solution was washed withwater and brine, dried over Na₂SO₄, concentrated, and flashchromatographed (0-60% EtOAc in hexane).(±)-3-(3,5-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoic acid 36 was obtained as a colorless oil. MS ESI (neg.) m/e:393 (M−H). ¹H NMR (500 MHz) (CDCl₃) δ 7.25-7.31 (m, 2H); 7.20-7.22 (m,2H); 7.14 (d, J =8.4 Hz, 2H); 6.87 (d, J=8.4 Hz, 2H); 6.78 (d, J =6.5Hz, 2H); 6.67 (t, J =8.9 Hz, 1H); 5.16 (m, 1H); 4.47 (t, J=7.8 Hz, 1H);3.38 (dd, J =16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.6 Hz, 2H); 3.06 (d,J =7.9 Hz, 2H).

6.52 Example 37

(±)3-(2,5-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoicacid (37). Compound 37 was prepared by a procedure analogous to thatdescribed for 36 using M8. MS ESI (neg.) m/e: 393 (M−H). ¹H NMR (500MHz) (CDCl₃) δ 7.20-7.30 (m, 6H); 6.86-7.01 (m, 5H); 5.15 (m, 1H); 4.76(t, J=7.8 Hz, 1H); 3.37 (dd, J=16.7, 6.3 Hz, 2H); 3.18 (dd, J=16.7, 2.5Hz, 2H); 3.09 (d, J =7.9 Hz, 2H).

6.53 Example 38

(±)3-(2,4-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoicacid (38). Compound 38 was prepared by a procedure analogous to thatdescribed for 36 using M7. MS ESI (neg.) m/e: 393 (M−H). ¹H NMR (500MHz) (CDCl₃) δ 7.16-7.29 (m, 7H); 6.77-6.86 (m, 4H); 5.15 (m, 1H); 4.74(t, J=8.0 Hz, 1H); 3.37 (dd, J=16.7, 6.3 Hz, 2H); 3.18 (dd, J=16.7, 2.7Hz, 2H); 3.09 (d, J=8.0 Hz, 2H).

6.54 Example 39

(±)3-(2,6-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoicacid (39). Compound 39 was prepared by a procedure analogous to thatdescribed for 36 using M9. MS ESI (neg.) m/e: 393 (M−H). ¹H NMR (500MHz) (CDCl₃) δ 7.01-7.30 (m, 7H); 6.84-6.89 (m, 4H); 5.14 (m, 1H); 4.92(t, J=8.0 Hz, 1H); 3.36 (dd, J=16.7, 6.3 Hz, 2H); 3.29 (dd, J=7.6, 5.5Hz, 2H); 3.17 (dd, J=16.7, 2.6 Hz, 2H).

6.55 Example 40

(±)3-(4-Fluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)propanoicacid (40). Compound 40 was prepared by a procedure analogous to thatdescribed for 36. MS ESI (neg.) m/e: 375 (M−H). ¹H NMR (500 MHz) (CDCl₃)δ 7.02-7.27 (m, 6H); 7.14 (d, J=8.5 Hz, 2H); 7.00 (t, J=8.6 Hz, 2H);6.85 (d, J=8.6 Hz, 2H); 5.15 (m, 1H); 4.49 (t, J=7.9 Hz, 1H); 3.37 (dd,J=16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.7 Hz, 2H); 3.06 (d, J=7.7 Hz,2H).

6.56 Example 41

(±)-3-[4-(5-Bromo-indan-1-yloxy)-phenyl]-3-phenyl-propionic acid (41).Compound 41 was prepared by a procedure analogous to that described for1.3 using M3. MS ESI (neg.) m/e: 437.0 (M−H). ¹HNMR (DMSO-d₆) δ 12.10(br, 1H), 7.54 (s, 1H), 7.43-7.41 (dd, 1H, J1=1.72 Hz, J2=8.07 Hz),7.34-7.16 (m, 8H), 6.94 (d, 2H, J=8.69 Hz), 5.76-5.73 (m, 1H), 4.39 (t,1H, J=8.03 Hz), 3.07-3.03 (m, 1H), 3.00 (d, 2H, J=7.96 Hz), 2.91-2.84(m, 1H), 2.57-2.55 (m, 1H), 2.04-1.97 (m, 1H).

6.57 Example 42

(±)-3-[4-(5-Bromo-indan-1-yloxy)-phenyl]-3-(4-fluoro-phenyl)-propionicacid (42). Compound 42 was prepared by a procedure analogous to thatdescribed for 1.3 using M2. MS ESI (neg.) m/e: 455.0 (M−H). ¹HNMR(DMSO-d₆) δ 12.09 (br, 1H), 7.53 (s, 1H), 7.42-7.40 (m, 1H), 7.36-7.29(m, 3H), 7.24 (d, 2H, J=8.50 Hz), 7.11 (t, 2H, J=9.00 Hz), 6.93 (d, 2H,J=8.50 Hz), 5.74-5.73 (m, 1H), 4.39 (t, 1H, J=8.00 Hz), 3.05-3.02 (m,1H), 2.99 (d, 2H, J=8.00 Hz), 2.91-2.84 (m, 1H), (1H overlaps withDMSO), 2.01-1.91 (m, 1H).

6.58 Examples 43-45

(S)-3-(4-((S)-5-Bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (44) and(S)-3-(4-((S)-5-bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (45). Racemic compound 43 was obtained as described in Example 2.Racemic 43 was separated on a preparatory chiral HPLC with CHIRALPAKAD-H column, using 50% i-PrOH in hexane as eluant. Eluant containing thepeak with greater retention time was concentrated and assigned as 44arbitrarily. MS ESI (neg.) M/E: 397.0, 399.1 (M−H). ¹HNMR (CDCl₃) δ 7.47(s, 1H), 7.39-7.32 (m, 3H), 7.29(m, 1H), 6.95 (d, 2H, J=8.50 Hz), 5.69(t, 1H, J=4.50 Hz), 4.09 (m, 1H), 3.13 (m, 1H), 2.94 (m, 1H), 2.87 (m,1H), 2.76 (m, 1H), 2.59 (m, 1H), 2.23 (m, 1H), 1.87, 1.86 (ss, 3H). Thepeak with shorter retention time was concentrated and assigned as 46.M/E: 397.0, 399.1 (M−H). ¹HNMR (CDCl₃) δ 7.48 (s, 1H), 7.39-7.33 (m,3H), 7.31(m, 1H), 6.96 (d, 2H, J=9.00 Hz), 5.69 (m, 1H), 4.09 (m, 1H),3.13 (m, 1H), 2.94 (m, 1H), 2.87 (m, 1H), 2.76 (m, 1H), 2.59 (m, 1H),2.23 (m, 1H), 1.87, 1.86 (ss, 3H).

6.59 Example 46

(3S)-3-(4-(2,3-Dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoic acid (46).Compound 46 was prepared by a procedure analogous to that described for14. MS ESI (neg.) m/e: 319.1 (M−H).

6.60 Example 47

5-Bromo-2,3-dihydro-1H-inden-1-ol (47.2). A mixture of5-bromo-2,3-dihydroinden-1-one (47.1) (23.7 mmol) and NaBH₄ (47.4 mmol)in EtOH (50 mL) was stirred at 60° C. for 6 minutes. After evaporationof the solvent, the residue was purified by chromatography (silica gel;1:2 EtOAc/hexane) providing compound 47.2 in 100% yield. MS ESI (pos.)M/E: 195.0, 197.1 (M+H—H₂O).

5-Bromo-1-chloro-2,3-dihydro-1H-indene (47.3). A mixture of 47.2 (11.1mmol) and thionyl chloride (44 mmol) in DCM (20 mL) was stirred at roomtemperature overnight. After evaporation of solvent, 47.3 was obtainedand it was used without further purification.

Methyl3-(4-(5-bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(1H-pyrazol-1-yl)propanoate(47.5). A mixture of 47.3 (0.16 mmol) and methyl3-(4-hydroxyphenyl)-3-(1H-pyrazol-1-yl)propanoate 47.4 (obtained by theprocedure of Example 58 set forth in US 2006/0004012 which is herebyincorporated by reference) (0.11 mmol) was stirred at 40° C. for 1 hour.After work up and chromatography, 47.5 was obtained in 30% yield. MS ESI(pos.) M/E: 441, 443 (M+H).

3-(4-(5-Bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(1H-pyrazol-1-yl)propanoicacid (47). Hydrolysis of 47.5 yielded 47 by the procedure of Example 18set forth in US 2006/0004012 which is hereby incorporated by reference).MS ESI (neg.) MIE: 425, 427 (M−H). ¹HNMR (DMSO-d₆) δ 7.85 (s, 1H), 7.56(s, 1H), 7.43 (m, 2H), 7.24-7.34 (m, 3H), 6.98 (d, 2H, J=9 Hz), 6.23 (s,1H), 5.80 (m, 2H), 3.07 (m, 1H), 2.92 (m, 1H).

6.61 Example 48

(±)-3-(4-(2,3-Dihydro-1H-inden-2-yloxy)phenyl)-3-(thiophen-2-yl)propanoicacid (48.1). A flask was charged with a stir bar, phenol M4 (168 mg,0.64 mmol), tributylphosphine (0.24 mL, 0.96 mmol), 2-indanol (111 mg,0.83 mmol), and benzene (5 mL). To the resulting solution, TMAD (165 mg,0.96 mmol) was added drop-wise via syringe. The resulting solution wasstirred at room temperature overnight. The reaction was concentrated andpurified via silica chromatography (4:1 hexane:EtOAc) to provide ester48.1 (70 mg). MS ESI (pos.) m/e: 379 (M+H).

To a solution of ester 48.1 (70 mg, 0.23 mmol) in THF/MeOH (2/0.7 mL)was added 2 N LiOH (0.5 mL, 1 mmol). The resulting solution was stirredat room temperature overnight. The solvent was removed in vacuo and theresulting residue was partitioned between 1N HCl and EtOAc. The solutionwas extracted one additional time with EtOAc. The combined organiclayers were concentrated, and the resulting residue was purified viareverse phase HPLC chromatography (ACN: Water+0.1% TFA) to provide 48(40 mg). MS ESI (pos.) m/e: 365 (M+H).

6.62 Example 49

(±)3-(4-(6,7,8,9-Tetrahydro-5H-benzo[7]annulen-5-yloxy)phenyl)-3-(thiophen-2-yl)propanoicacid (49). A flask was charged with a stir bar, phenol M4 (107 mg, 0.41mmol), tributylphosphine (0.15 mL, 0.61 mmol),6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol (86 mg, 0.53 mmol), andbenzene (5 mL). To the resulting solution, TMAD (105 mg, 0.61 mmol) wasadded drop-wise via syringe. The resulting solution was stirred at roomtemperature overnight. The reaction was concentrated and purified viasilica chromatography (4:1 hexane: ethyl acetate) providing ester 49.1(101 mg). MS ESI (pos.) m/e: 407 (M+H). To a solution of ester 49.1 (70mg, 0.23 mmol) in THF/MeOH (2/0.7 mL) was added 2 N LiOH (0.5 mL, 1mmol). The resulting solution was stirred at room temperature overnight.The solvent was removed in vacuo and the resulting residue waspartitioned between 1 N HCl and EtOAc. The solution was extracted oneadditional time with EtOAc. The combined organic layers wereconcentrated, and the resulting residue was purified via reverse phaseHPLC chromatography (ACN:Water+0.1% TFA) providing 49 (60 mg). MS ESI(pos.) m/e: 393 (M+H).

6.63 Example 50

(3S)-3-(4-(5-(3-(Trifluoromethoxy)phenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (50) Compound 50 was prepared by a procedure analogous to thatdescribed for 3 using the boronic acid shown. MS ESI (neg.) m/e: 479.2(M−H). ¹HNMR (DMSO-d₆) δ 12.21 (br, 1H), 7.80 (d, 2H, J=8.83 Hz), 7.63(s, 1H), 7.56-7.46 (m, 4H), 7.32 (d, 2H, J=8.69 Hz), 7.03 (d, 2H, J=8.69Hz), 5.88 (m, 1H), 3.96 (m, 1H), 3.08 (m, 1H), 2.96 (m, 1H), 2.62 (m,3H), 2.10 (m, 1H), 1.81, 1.80 (ss, 3H).

6.64 Example 51

Ethyl3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate(51.1). A mixture of M5 (obtained by the procedure of Example 60 setforth in US 2006/0004012 which is hereby incorporated by reference)(0.25 mmol), 2,3-dihydro-1H-inden-2-yl 4-methylbenzenesulfonate (0.38mmol) and Cs₂CO₃ (0.5 mmol) in DMF (3 mL) was stirred at 130° C. for 4hours. After work up and chromatography (silica gel; 1:2 EtOAc/hexane),compound 51.1 was obtained in 26% yield. MS ESI (pos.) M/E: 392 (M+H).

3-(4-(2,3-Dihydro-1H-inden-2-yloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoicacid (51). Hydrolysis of 51.1 yielded 51 using the procedure of Example18 set forth in US 2006/0004012 which is hereby incorporated byreference. MS ESI (neg.) M/E: 362 (M−H). ¹HNMR (DMSO-d₆) δ 7.25 (m, 2H),7.16 (m, 4H), 6.89 (m, 2H), 6.73 (s, 1H), 5.20 (m, 1H), 4.43 (m, 1H),3.07 (m, 1H), 2.75 (m, 1H), 2.22 (s, 3H).

6.65 Examples 52 and 53

6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-1-one (52.3).6-Hydroxy-1-tetralone (52.1)(3.24 g, 20 mmol) and 4-methoxybenzylchloride (52.2) (3.13 g, 20 mmol) were dissolved in DMF (20 mL). Cs₂CO₃(7.17 g, 22mmol) was added to the mixture, and the resulting mixture wasstirred overnight at ambient temperature. The reaction mixture wasdiluted with water (200 mL) and extracted with ethyl acetate (50 mL×3).The combined organic layers were washed with saturated brine, dried overMgSO₄, filtered, and concentrated under reduced pressure. The residuewas used without further purification for the next step. MS ESI (pos.)m/e: 283 (M+1)⁺.

[6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-aceticacid (52.4). A solution of ethyl (trimethylsilyl)acetate (12.07 g, 75mmol) in anhydrous THF (60 mL) at −78° C. was treated dropwise withLiHMDS (1M in THF, 66 mL). The resulting mixture was stirred at −78° C.for 30 minutes. A solution of 52.3 (14.0 g, 50 mmol) in THF (10 mL) wasadded to the mixture over 20 minutes. The resulting mixture was stirredat −78° C. for 2 hours before warming to 0° C. The reaction mixture wasquenched with NH₄Cl (sat. 200 mL) and extracted with ethyl acetate (70mL×4). The combined organic layers were washed with saturated brine,dried over MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash chromatography (silica gel, 30% ethylacetate in Hexane).[6-(4-Methoxy-benzyloxy)-3,4-dihydro-2H-naphthalen-(1E)-ylidene]-aceticacid (52.4) was obtained as a light yellow oil (12.2 g, 69% yield). MSESI (pos.) m/e: 353 (M+1)⁺.

(R/S)-(6-Hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid ethylester (52.5). Compound 52.4 (6.2, 17.6 mmol) was dissolved in MeOH (30mL). Pd/C (10%, 620 mg) was added to the solution carefully. A H₂balloon was connected to the reaction flask. The resulting mixture wasstirred overnight at ambient temperature. The Pd/C was filtered away,and the filtrate was concentrated under reduced pressure.(R/S)-(6-Hydroxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-acetic acid ethylester (52.5) was obtained as a clear oil (3.75 g, 91%). MS ESI (pos.)m/e: 235 (M+1)⁺ and 257 (M+Na)⁺. ¹H NMR (400MHz) (CDCl₃) δ 7.02 (d, 1H);6.64 (d, 1H); 6.56 (s, 1H); 5.04 (d, 1H); 4.20 (q, 2H); 3.31 (m, 1H);2.73 (m, 2H); 2.54 (m, 2H); 1.71 (m, 4H); 1.29 (t, 3H).

(R/S) Ethyl2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate(52). Tributyl phosphine (137 mg, 0.68 mmol) and TMAD (122 mg, 0.68mmol) were added successively to a dry benzene (10 mL) solution of2-indanol (92 mg, 0.68 mmol) and ethyl2-(6-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetate 52.5 (160 mg,0.68 mmol) with stirring under a nitrogen atmosphere. The reactionmixture was stirred at room temperature for 2 days. The product wasisolated by silica gel column chromatography after filtration andevaporation of the solvent in vacuo. (R/S)-Ethyl2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate(52) was obtained as a colorless oil (85 mg, 35%). LC-MS ESI (pos.) m/e:351 (M+H).

(R/S)-2-(6-(2,3-Dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)aceticacid (53). A mixture of (R/S)-ethyl2-(6-(2,3-dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)acetate52 (85 mg, 0.24 mmol) and LiOH (40 mg) in THF- H2O (1/1, 4 mL) wasstirred at room temperature for 6 hours. 2N HCl was added to acidify themixture to pH 2-3. The mixture was then extracted with EtOAc (2×20 mL).The combined organic layers were washed with water and brine, and driedover Na₂SO₄. The residue obtained after filtration and concentration waspurified with flash chromatography (0-60% EtOAc in hexane).(R/S)-2-(6-(2,3-Dihydro-1H-inden-2-yloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)aceticacid (53) was obtained as colorless oil (79 mg, 96%). MS ESI (neg.) m/e:321 (M−H). ¹H NMR (500 MHz) (CDCl₃) δ 7.11-7.28 (m, 5H); 6.65-6.75 (m,2H); 5.16 (m, 1H); 3.36-3.40 (m, 3H); 3.19 (dd, J=16.6, 3.0 Hz, 2H);2.62-2.80 (m, 3H), 2.59 (q, J=9.9 Hz, 1H), 1.99 (m, 1H), 1.78-1.87 (m,3H).

6.66 Example 54

(3S)-3-(4-(5-Cyano-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoic acid(54). Compound 54 was prepared by a procedure analogous to thatdescribed for 14. MS: 344.2 (M−1). ¹HNMR (DMSO-d₆) ppm 12.25 (br, 1H),7.81 (s, 1H), 7.70 (d, 1H, J=8.00 Hz), 7.56 (d, 1H, J=8.00 Hz), 7.30 (d,2H, J=8.50 Hz), 7.00 (d, 2H, J=8.50 Hz), 5.89 (t, 1H, J=5.50 Hz), 3.96(m, 1H), 3.07 (m, 1H), 2.95 (m, 1H), 2.62 (m, 3H), 2.04 (m 1H), 1.78,1.79(ss, 3H).

6.67 Example 55

(3S)-3-(4-(5-(2-Fluoro-5-methoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (55). Compound 55 was made from M1 by a sequence analogous to thatused for Example 59 with the appropriate boronic acid.

6.68 Example 56

(S)-3-{4-[5-(2-Fluoro-5-methoxy-phenyl)-indan-1-yloxy]-phenyl}-5-methyl-hex-4-enoicacid ethyl ester (56). Compound 56 was made from M15.3 by a sequenceanalogous to that used for Example 59 with the appropriate boronic acid.

6.69 Example 57

(R)-3-{4-[5-(2-Fluoro-5-methoxy-phenyl)-indan-1-yloxy]-phenyl}-5-methyl-hex-4-enoicacid ethyl ester (57). Compound 57 was made from M15.4 by a sequenceanalogous to that used for Example 59 with the appropriate boronic acid.

6.70 Example 58

(3S)-3-(4-(5-Chloro-2,3-dihydro-1H-inden-1-yloxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (58) To a mixture of compound M12 (150 mg, 0.54 mmol),5-chloroindan-1-ol (180 mg, 1.07 mmol), and tributylphosphine (0.40 mL,1.62 mmol) in THF (5 mL) was addedN,N,N′,N′-tetramethylazodicarboxamide(TMAD) (0.27 g, 1.56 mmol). Thereaction mixture was stirred at room temperature overnight. The reactionmixture was quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column to afford the ester 58.1. Theester was hydrolyzed to compound 58 by the general procedure B (Example1). MS ESI (pos.) m/e: 397.1 (M+H). ¹HNMR (MeOH-d₄) δ 7.29 (d, 1H, J=5.0Hz), 7.28 (br, 1H), 7.19-7.16 (m, 3H), 7.12 (m, 2H), 6.96 (d, 2H, J=10.0Hz), 5.71 (m, 1H), 4.69 (m, 1H), 3.61 (s, 3H), 3.30 (m, 1H), 3.03 (m,1H), 2.98 (m, 1H), 2.88 (m, 1H), 2.54 (m, 1H), 2.09 (m, 1H).

6.71 Example 59

(3R)-Methyl3-(4-(5-bromo-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoate (59.2)Compound 59.2 was prepared from compound 59.1 by following the sameprocedure for M1 of Method 1 except obtaining the different enantiomer.MS ESI (neg.) M/E: 411.0 (M−H).

6.71.1 General Procedure C: Suzuki Coupling

(3R)-Methyl3-(4-(5-(3-ethoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoate(59.3). A mixture of 59.2 (30 mg, 0.073 mmol), 3-ethoxyphenylboronicacid (14.5 mg, 0.087 mmol) and CsF (55 mg, 0.36 mmol) in1,2-dimethoxyethane (2 mL) was degassed with N₂ for 3 minutes. Pd(PPh₃)₄(20 mg, 0.017 mmol) was added, and the resulting mixture was heated to95° C. for 8 hours. After cooling, the reaction mixture was quenchedwith water and extracted with EtOAc to obtain the ester 59.3, which wasdirectly hydrolyzed in next step.

6.71.2 General Procedure D: Alkaline Hydrolysis

(3R)-3-(4-(5-(3-Ethoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (59). A solution of 59.3 in THF/MeOH (1:1, 2 mL), was treated with2N NaOH aqueous solution (1 mL) and stirred for overnight at roomtemperature. The reaction mixture was acidified with aqueous 4N HCl andextracted with EtOAc to obtain 59, which was purified by preparativeHPLC, eluting with 5˜95% ACN in water containing 0.1% TFA. MS ESI (neg.)m/e: 439.1 (M−H). ¹HNMR (MeOD-d₄) δ 7.65 (br, 1H), 7.48 (s, 1H), 7.38(d, 1H, J=7.02 Hz), 7.32 (t, 1H, J=7.12 Hz), 7.18 (d, 1H, J=6.57 Hz),7.14 (s, 1H), 7.06 (m, 2H), 6.99-6.86 (m, 2H), 6.78 (m, 1H), 4.79 (m,1H), 4.12(q, 2H, J=6.50 Hz), 3.86 (m, 1H), 3.15-3.01 (m, 2H), 2.54-2.42(m, 2H), 2.03 (m, 1H), 1.74 (ss, 3H), 1.42 (t, 3H, J=6.74 Hz).

6.72 Example 60

(3R)-3-(4-(5-(Benzo[d][1,3]dioxol-5-yl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (60) Compound 60 was prepared by a procedure analogous to thatdescribed for Example 59 using the boronic acid shown MS ESI (neg.) m/e:439.1 (M−H). ¹HNMR (MeOD-d₄) δ 7.66 (m, 1H), 7.46 (br, 1H), 7.32 (d, 1H,J=6.02 Hz), 7.16-7.01 (m, 4H), 6.92-6.89 (m, 2H), 6.78 (d, 1H, J=6.96Hz), 5.98 (s, 2H), 4.75 (m, 1H), 3.85 (m, 1H), 3.06-2.97 (m, 2H),2.72-2.54 (m, 3H), 2.19 (m, 1H), 1.74 (ss, 3H).

6.73 Example 61

(3R)-3-(4-(5-(2,3-Dimethoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (61) Compound 61 was prepared by a procedure analogous to thatdescribed for Example 59 using the boronic acid shown. MS ESI (neg.)m/e: 455.2 (M−H). ¹HNMR (MeOD-d₄) δ 7.64 (m, 1H), 7.56 (m, 1H), 7.42 (s,1H), 7.27 (m, 1H), 7.10 (m, 1H), 7.03-6.94 (m, 4H), 6.79 (dd, 1H,J1=8.21 Hz, J2=2.54 Hz), 4.75 (m, 1H), 3.90 (s, 3H), 3.86 (m, 1H), 3.59(s, 3H), 3.06-2.97 (m, 2H), 2.61-2.52 (m, 3H), 2.02 (m, 1H), 1.75 (ss,3H).

6.74 Example 62

(3R)-3-(4-(5-(3-Methoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (62) Compound 62 was prepared by a procedure analogous to thatdescribed for 59 using the boronic acid shown. MS ESI (neg.) m/e: 425.2(M−H). ¹HNMR (MeOD-d₄) δ 7.59 (s, 1H), 7.40-7.31 (m, 2H), 7.21-7.15 (m,2H), 7.06 (m, 2H), 6.94-6.88 (m, 2H), 6.77 (d, 1H, J=5.52 Hz), 6.65 (m,1H), 4.78 (m, 1H), 3.86 (s, 3H), 3.78 (m, 1H), 3.09-2.97 (m, 2H),2.63-2.53 (m, 3H), 2.04 (m, 1H), 1.74 (ss, 3H).

6.75 Example 63

(3R)-3-(4-(5-(3-(trifluoromethoxy)phenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (63) Compound 63 was prepared by a procedure analogous to thatdescribed for 59 using the boronic acid shown. MS ESI (neg.) m/e: 479.1(M−H). ¹HNMR (MeOD-d₄) δ 7.64 (d, 1H, J=7.69 Hz), 7.54-7.50 (m, 3H),7.41 (d, 1H, J=7.82 Hz), 7.23 (d, 1H, J=8.19 Hz), 7.11-7.05 (m, 2H),6.93 (m, 1H), 6.78 (dd, 1H, J=8.25 Hz, J2=2.48 Hz), 4.78 (m, 1H), 3.86(m, 1H), 3.15-2.99 (m, 2H), 2.63-2.51 (m, 3H), 2.06 (m, 1H), 1.74 (ss,3H).

6.76 Example 64

(3R)-3-(4-(5-Mesityl-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (64) Compound 64 was prepared by a procedure analogous to thatdescribed for 59 using the boronic acid shown. MS ESI (neg.) m/e: 437.2(M−H). ¹HNMR (MeOD-d₄) δ 7.07-7.02 (m, 3H), 6.96 (s, 1H), 6.90-6.84 (m,4H), 6.78 (m, 1H), 4.78 (m, 1H), 3.87 (m, 1H), 3.03-2.96 (m, 2H),2.59-2.53 (m, 3H), 2.30 (s, 3H), 2.03(br, 6H), 2.00 (br, 1H), 1.74 (ss,3H).

6.77 Example 65

(3R)-3-(4-(5-(2-Ethoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (65) Compound 65 was prepared by a procedure analogous to thatdescribed for 59 using the boronic acid shown. MS ESI (neg.) m/e: 439.1(M−H). ¹HNMR (MeOD-d₄) δ 7.71-7.54 (m, 1H), 7.43 (br, 1H), 7.39-7.27 (m,3H), 7.05-6.92 (m, 5H), 6.78 (m, 1H), 4.78 (m, 1H), 4.05(q, 2H, J=6.85Hz), 3.86 (m, 1H), 3.18-2.99 (m, 2H), 2.63-2.53 (m, 3H), 2.05 (m, 1H),1.75 (ss, 3H), 1.34 (t, 3H, J=6.29 Hz).

6.78 Example 66

(3R)-3-(4-(5-(5-Ethoxy-2-fluorophenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (66) Compound 66 was prepared by a procedure analogous to thatdescribed for 7 using the boronic acid shown. MS ESI (neg.) m/e: 457.1(M−H). ¹HNMR (MeOD-d₄) δ 7.45 (s, 1H), 7.31 (d, 1H, J=7.71 Hz),7.10-6.92 (m, 5H), 6.87 (m, 1H), 6.80 (m, 1H), 4.78 (m, 1H), 4.05 (q,2H, J=6.85 Hz), 3.87 (m, 1H), 3.07-2.99 (m, 2H), 2.63-2.53 (m, 3H), 2.04(m, 1H), 1.74 (ss, 3H), 1.39 (t, 3H, J=6.72 Hz).

6.79 Example 67

(3R)-3-(4-(5-(2-Fluoro-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-yloxy)phenyl)hex-4-ynoicacid (67) Compound 67 was prepared by a procedure analogous to thatdescribed for 59 using the boronic acid shown. MS ESI (neg.) m/e: 443.2(M−H). ¹HNMR (DMSO-d₆) δ 12.15 (br, 1H), 7.43 (s, 1H), 7.28 (d, 1H,J=7.55 Hz), 7.22-7.14 (m, 2H), 7.04-6.90 (m, 4H), 6.18 (m, 1H), 4.65 (m,1H), 3.81 (s, 3H), 3.78 (m, 2H), 3.04-2.92 (m, 2H), 2.04 (m, 1H), 1.72(ss, 3H).

6.80 Example 68

(R)-3-(4-(Cyclohexylmethoxy)phenyl)hex-4-ynoic acid (68). Compound 59.1(30 mg, 0.14 mmol) was dissolved in DMF (1 mL), and Cs₂CO₃ (89 mg, 0.27mmol), and cyclohexylmethyl bromide (29 uL, 0.20 mmol) were added. Thereaction was left to stir at room temperature overnight. The reactionwas then blown dry and extracted with EtOAc. The compound was thenpurified with 5-10% EtOAc on a silica gel column to provide the ester68.1. Ester 68.1 was hydrolyzed to provide acid 68 by general procedureD. ESI (neg.) m/e: 299.0 (M−H).

6.81 Example 69

(S)-3-(4-(2-cyclohexylethoxy)phenyl)hex-4-ynoic acid (69). Compound 69was prepared from M1 by a procedure analogous to that described forExample 14 except DEAD and triphenylphosphine were utilized instead ofTMAD and tributylphosphine. MS ESI (neg.) m/e: 313.1 (M−H). ¹HNMR(CDCL₃) δ 7.28 (d, 2H, J=8.61), 6.85 (d, 2H, J=8.61), 4.05 (m, 1H), 3.98(t, 2H, J=6.65 Hz), 2.80 (dd, 1H, J=8.61, 15.65), 2.71 (dd, 1H, J=6.65,15.65), 1.83 (d, 3H, J=2.35), 1.80-1.63 (m, 7H), 1.56-1.46 (m, 1H),1.33-1.11 (m, 3H), 1.04-0.92 (m, 2H).

6.82 Example 70

(S)-3-(4-(2-cyclopentylethoxy)phenyl)hex-4-ynoic acid (70). Compound 70was prepared from M1 by a procedure analogous to that described forExample 14 except DEAD and triphenylphosphine were utilized instead ofTMAD and tributylphosphine. MS ESI (neg.) m/e: 299.2 (M−H). ¹HNMR(CDCL₃) δ 7.28 (d, 2H, J=8.61), 6.85 (d, 2H, J=8.61), 4.05 (m, 1H), 3.96(t, 2H, J=6.65 Hz), 2.80 (dd, 1H, J=8.22, 15.65), 2.71 (dd, 1H, J=6.65,15.65), 2.00-1.90 (m, 1H), 1.83 (d, 3H, J=2.35), 1.85-1.75 (m, 4H),1.67-1.50 (m, 4H), 1.23-1.11 (m, 2H).

6.82.1 General Procedure E: Reaction of the Various Headgroups with6-halomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene

A mixture of phenol (0.18 mmol),6-halomethyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (0.2mmol) or another benzyl chloride or benzyl bromide compound, and cesiumcarbonate (0.27 mmol) in DMF (2 mL), was/is stirred at room temperatureovernight. The reaction mixture was/is diluted with water and extractedinto DCM. The separated DCM layer was/is washed with water. The residueobtained after concentration was/is dissolved into THF and MeOH (1 mLeach) and treated with 2 M NaOH solution (0.45 mL, 0.9 mmol). Theresulting solution was/is further stirred for 16-48 hours at roomtemperature. The reaction mixture was/is concentrated, and the residuewas/is dissolved in a mixture of DMF/ACN (1:4, 5 mL) containing TFA (67μL, 0.9 mmol). This solution was/is filtered and purified by preparatoryHPLC. The solvent was/is evaporated by freeze-drying to provide thedesired product generally as a white amorphous solid.

6.83 Example 71

(S)-3-(1-Methyl-1H-imidazol-2-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (71). Compound 71 was obtained from compound M12 using the generalProcedure E. MS ESI (neg.) M/E: 445 (M−H). ¹HNMR (DMSO-d₆) δ 7.65 (s,1H), 7.6 (s, 1H), 7.3 (overlapping m, 2H), 7.20 (d, 2H), 7.1 (d, 1H),7.0 (d, 2 H), 5.0 (s, 2H), 4.85 (m, 1H), 3.8 (s, 1H), 3.1 (dd, 1H), 1.6(s, 4H), 1.2 (s, 12H).

6.84 Example 72

(S)-3-(2-Methyl-2H-[1,2,4]triazol-3-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (72). Compound 72 was obtained from compound 72.1 (M13) byfollowing the general Procedure E. MS ESI (neg.) M/E: 446 (M−H). ¹HNMR(DMSO-d₆) δ 7.75 (s, 1H), 7.2 (m, 2H), 7.12 (s, 2H), 7.08 (d, 1H), 6.85(d, 2H), 4.9 (s, 2H), 4.5 (m, 1H), 3.6 (s, 3H), 3.1 (dd, 1H), 2.7 (dd,1H), 1.55 (s, 4H), 1.15 (s, 12H).

6.85 Example 73

This example illustrates the preparation of(S)-3-(3-methyl-3H-1,2,3-triazol-4-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (73).

1-methyl-1H-1,2,3-triazole (73.1). A mixture of2-(trimethylsilyl)-2H-1,2,3-triazole (179 mmol), MeI (179 mmol), andTBAF on silica gel (16.3 mmol) in ACN (200 mL), was refluxed for 4hours. After cooling to room temperature, the mixture was concentratedwith silica gel and chromatographed (silica gel, 5:95 MeOH/DCM). Thefractions containing product were collected, concentrated, and distilledunder vacuum to give desired product 1.1 (7.5 g, 90 mmol, b.p.=97° C. at3 mmHg). MS ESI (pos.) m/e 83.9 (M+H).

(4-(Benzyloxy)phenyl)(3-methyl-3H-1,2,3-triazol-4-yl)methanol (73.2). Asolution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was addeddropwise to a solution of 73.1 (1.29 g, 15.5 mmol) in THF (75 mL) at−40° C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehydewas added at −40° C., and the reaction was warmed to room temperature.The reaction was quenched saturated NH₄Cl (aq) after 3 hours of stirringand then extracted with EtOAc. The organic phase was washed with waterand brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue 73.2 was used in thenext reaction without further purification. MS ESI (pos.) m/e 296.2(M+H).

(4-(Benzyloxy)phenyl)(3-methyl-3H-1,2,3-triazol-4-yl)methanone (73.3).Dess-Martin periodinane (8 g, 19 mmol) was added to a solution of 73.2(˜15.5 mmol) in DCM (80 mL). After 1 hour, the reaction mixture wasconcentrated with silica gel and chromatographed (silica gel, 1:2EtOAc/hexane) to obtain compound 73.3 (4.3 g, 14.7 mmol). MS ESI (pos.)m/e: 294.1 (M+H).

Ethyl 3-(4-(benzyloxy)phenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)acrylate(73.4). To a solution of lithium bis(trimethylsilyl)amide (22 mmol, 1 Min THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 73.3 (14.7 mmol) inTHF (50 mL) was added dropwise, and the reaction was maintained at −78°C. for 4 hours. The reaction was quenched with saturated NH₄Cl (aq) andwarmed to room temperature. The mixture was extracted with EtOAc (500mL), dried over anhydrous sodium sulfate, filtered, and concentratedwith silica gel under reduced pressure. The residue was chromatographed(silica gel, 1:1 EtOAc/hexane) to afford compound 73.4 (5.1 g, 14 mmol).MS ESI (pos.) m/e 364.1 (M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)propanoate(73.5). 73.4 was dissolved in EtOH and stirred with Pd—C (1.48 g, 0.7mmol) under hydrogen at room temperature for 3 hours. The Pd—C wasremoved by filtration through celite with EtOAc as eluant. Afterconcentration, the residue was chromatographed (silica gel, 1:1EtOAc/hexane) to afford compound 3.5 (3.28 g, 12 mmol). MS ESI (pos.)m/e 276.1 (M+H).

(S)-ethyl3-(4-hydroxyphenyl)-3-(3-methyl-3H-1,2,3-triazol-4-yl)propanoate (73.6).Racemic compound 73.5 (3.28 g, 12 mmol) was separated on asemi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 30%i-PrOH in hexane as eluant. Eluant containing the peak with lessretention time was concentrated and compound 73.6 (1.5 g, 5.45 mmol) wasobtained as off-white solid. The absolute configuration was assigned byanalogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 276.1 (M+H).

(S)-3-(3-methyl-3H-1,2,3-triazol-4-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (73). A mixture of 73.6 (0.15 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.18mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at roomtemperature for 16 hours. To the reaction mixture was added LiOH inwater (1 mL, 1N solution), and the resulting mixture was stirred at 50°C. for 3 hours. The mixture was filtered and purified by reverse phaseHPLC to give 73 (26 mg, 0.06 mmol) after lyophilization. MS ESI (pos.)m/e 448.3 (M+H). ¹H NMR (500 MHz) (CDCl₃) δ 7.95 (1 H, s), 7.71 (1 H,s), 7.33-7.36 (2 H, m), 7.20 (1 H, dd, J=7.9, 1.5 Hz), 7.07 (2 H, d,J=8.5 Hz), 6.97 (2 H, d, J=8.9 Hz), 4.98(2 H, s), 4.51-4.55(1 H, m),3.86(3 H, s), 3.11-3.17 (1 H, m), 3.01-3.07(1 H, m), 1.72(4 H, s), 1.31(6 H, s) 1.30(6 H, s).

6.86 Example 74

This example illustrates the preparation of(S)-3-(1-methyl-1H-imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (74).

(1-Methyl-1H-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol(74.1). 4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (110 mL, 0.5M in THF, 55 mmol) was added dropwise to a solution of1-methyl-1H-imidazole-5-carbaldehyde (4.7 g, 50 mmol) in THF (790 mL) at−78° C. After stirring −78° C. for 2 hours, the reaction was quenchedwith saturated NH₄Cl (aq) and warmed to room temperature. The mixturewas extracted with EtOAc (500 mL), and the organic phase was washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to give 14 g of the crude product74.1, which was used in the next reaction without further purification.

(1-Methyl-1H-imidazol-5-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone(74.2). Dess-Martin periodinane (21 g, 50 mmol) was added to a solutionof 74.1 (14 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, thereaction mixture was concentrated with silica gel and chromatographed(silica gel, 1:2 EtOAc/hexane) to provide compound 74.2 (3.3 g, 11.5mmol). MS ESI (pos.) m/e: 287.1 (M+H).

Ethyl3-(1-methyl-1H-imidazol-5-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(74.3). To a solution of lithium bis(trimethylsilyl)amide (6.8 mmol, 1 Min THF) was added ethyl trimethylsilylacetate (6.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 74.2 (5.9 mmol) inTHF (20 mL) was added dropwise. The reaction was maintained at −78° C.for 3 hours and at −45° C. for 2 hours. The reaction was quenched withsaturated NH₄Cl (aq) at 0° C. and warmed to room temperature. Themixture was extracted with EtOAc (500 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to affordcrude 74.3 (2.49 g). MS ESI (pos.) m/e 357.2 (M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-5-yl)propanoate(74.4). The crude 74.3 was dissolved in EtOH (50 mL), stirred with Pd—C(1.48 g, 0.7 mmol) under hydrogen at room temperature for 60 hours. ThePd—C was removed by filtration through celite with EtOAc as eluant.After concentration, the residue was treated with TFA (2 mL) in dry DCM(20 mL) at room temperature for 2 hours. The reaction mixture wasconcentrated then redissolved in DCM, washed with water, washed withsaturated NaHCO₃, dried over Na₂SO₄, and concentrated under reducedpressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane)to afford compound 74.4 (700 mg, 2.6 mmol). MS ESI (pos.) m/e 275.2(M+H).

(S)-ethyl 3-(4-hydroxyphenyl)-3-(1-methyl-1H-imidazol-5-yl)propanoate(74.5). Racemic compound 74.4 (680 mg, 2.5 mmol) was separated on asemi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 15%i-PrOH in hexane as eluant. Eluant containing the peak with lessretention time was concentrated and compound 74.5 (300 mg, 1.1 mmol) wasobtained as off-white solid. The absolute configuration was assigned byanalogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).

(S)-3-(1-methyl-1H-imidazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (74). A mixture of 74.5 (0.15 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.18mmol) and cesium carbonate (0.2 mmol) in DMF (2 mL), was stirred at roomtemperature for 16 hours. To the reaction mixture was added LiOH inwater (1 mL, 1N solution), and the reaction was stirred at 50° C. for 3hours. The mixture was filtered and purified by reverse phase HPLC togive 74 (35 mg, 0.08 mmol) after lyophilization. MS ESI (pos.) m/e 447.3(M+H). ¹H NMR (500 MHz) (CDCl₃) δ 8.64 (1 H, s), 7.59 (1 H, s),7.33-7.36 (2 H, m), 7.20 (1 H, dd, J=7.9, 1.8 Hz), 7.08 (2 H, d, J=8.5Hz), 6.98 (2 H, d, J=8.5 Hz), 4.98 (2 H, s), 4.53 (1 H, m), 3.57 (3 H,s), 2.96-3.06 (2 H, m), 1.71 (4 H, s), 1.31 (6 H, s), 1.30 (6 H, s).

6.87 Example 75

This example illustrates the preparation of(S)-3-(oxazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (75).

Oxazol-5-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanol (75.1).4-(2-Tetrahydro-3H-pyranoxy)phenylmagnesium bromide (120 mL, 0.5 M inTHF, 60 mmol) was added dropwise to a solution of oxazole-4-carbaldehyde(4.85 g, 50 mmol) in THF (90 mL) at −78° C. After stirring at −78° C.for 21 hours, the reaction was quenched with saturated NH₄Cl (aq) andwarmed to room temperature. The mixture was extracted with EtOAc (500mL), the organic phase was washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to give 17 g of the crude product 75.1, which was used in thenext reaction without further purification.

Oxazol-5-yl(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (75.2).Dess-Martin periodinane (25 g, 60 mmol) was added to a solution of 75.1(17 g crude, ˜50 mmol) in DCM (200 mL). After 1 hour, the reactionmixture was concentrated with silica gel and chromatographed (silicagel, 1:2 EtOAc/hexane) to obtain compound 75.2 (5.74 g, 21 mmol). MS ESI(pos.) m/e: 274.1 (M+H).

Ethyl 3-(oxazol-5-yl)-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)acrylate(75.3). To a solution of lithium bis(trimethylsilyl)amide (31.5 mmol, 1M in THF) was added ethyl trimethylsilylacetate (31.5 mmol) dropwise at−78° C. After 20 minutes at −78° C., a solution of 75.2 (21 mmol) in THF(60 mL) was added dropwise and the reaction was maintained at −78° C.for 1.5 hours. The reaction was quenched saturated NH₄Cl (aq) and warmedto room temperature. The mixture was extracted with EtOAc (500 mL), theorganic phase was washed with water and brine, dried over anhydroussodium sulfate, filtered, and concentrated with silica gel under reducedpressure. The residue was chromatographed (silica gel, 1:1 EtOAc/hexane)to afford compound 75.3 (4.83 g, 14 mmol). MS ESI (pos.) m/e 344.2(M+H).

Ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (75.4). TFA (10 mL)was added to a solution of 75.3 (14 mmol) in dry DCM (100 mL) andstirred at room temperature for 2 hours. To the reaction mixture wasslowly added solid NaHCO₃ with stirring. The reaction was then washedwith saturated NaHCO₃ (2×), dried over Na₂SO₄, and concentrated underreduced pressure. The residue was then re-dissolved in EtOH, stirredwith Pd—C (1.48 g, 0.7 mmol) under hydrogen at room temperature for 14hours. The Pd—C was removed by filtration through celite with EtOAc aseluant. After concentration, the residue was chromatographed (silicagel, 1:1 EtOAc/hexane) to afford compound 75.4 (1.3 g, 5 mmol). MS ESI(pos.) m/e 262.1 (M+H).

(S)-ethyl 3-(4-hydroxyphenyl)-3-(oxazol-5-yl)propanoate (75.5). Racemiccompound 75.4 (1.3 g, 5 mmol) was separated on a semi-preparatory chiralCHIRALCEL OJ-H column (30×250 mm), using 20% i-PrOH in hexane as eluant.Eluant containing the peak with greater retention time was concentratedand compound 75.5 (620 mg, 2.38 mmol) was obtained as off-white solid.The absolute configuration was assigned by analogy to other GPR40agonist compounds. MS ESI (pos.) m/e 262.1 (M+H).

(S)-3-(Oxazol-5-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (75). A mixture of 75.5 (0.1 mmol),6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (0.12mmol) and cesium carbonate (0.15 mmol) in DMF (2 mL) was stirred at roomtemperature for 3 hours. To the reaction mixture was added LiOH in water(1 mL, 1N solution), and the reaction was stirred at 50° C. for 3 hours.The mixture was filtered and purified by reverse phase HPLC to give 75(12 mg, 0.03 mmol) after lyophilization. MS ESI (pos.) m/e 434.2 (M+H).¹H NMR (500 MHz) (CDCl₃) δ 7.94 (s, 1H); 7.31-7.41(m, 3H); 7.22 (d,J=8.5 Hz, 2H); 6.99 (d, J=8.5 Hz, 2H); 6.87 (s, 1H); 4.99 (s, 2H); 4.58(t, J=7.9 Hz, 1H); 3.14 (dd, J=16.5, 7.6 Hz, 1H); 2.99 (dd, J=16.5, 7.6Hz, 1H); 1.72 (s, 4H); 1.31 (s, 12H).

6.88 Example 76

Synthesis of(S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (76).

(E)-4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)acrylate (76.2).Potassium carbonate (21 g, 152 mmol) was added to a mixture of4-hydroxycinnamic acid 76.1 (6.25 g, 38.1 mmol) and p-methoxy benzylchloride (10.35 mL, 76 mmol) in DMF (100 mL). The mixture was stirred at80° C. for five hours. After cooling, the mixture was poured into water(700 mL). The solid was collected by filtration, washed with water anddried to give 76.2 (15 g). MS ESI (pos.) m/e: 405 (M+H). ¹HNMR (CDCl₃) δ7.68(d, 1H), 7.47(d, 2H), 7.38(m, 4H), 6.95(m, 6H), 6.35(d, 1H), 5.20(s,2H), 5.03(s, 2H), 3.84(s, 3H), 3.83(s, 3H).

4-Methoxybenzyl 3-(4-(4-methoxybenzyloxy)phenyl)-4-nitrobutanoate(76.3). 1,1,3,3-tetramethylguanidine (0.31 mL, 2.48 mmol) was added to76.2 (5 g, 12.4 mmol) in nitromethane (20 mL). The mixture was stirredat room temperature for 3 hours, at 50° C. for 3 hours, and at 100° C.for 8 hours. Nitromethane was removed under vacuum and the crude productwas purified by flash chromatography to give 76.3 (4.5 g). MS ESI (pos.)m/e: 466 (M+H). ¹HNMR (CDCl₃) δ 7.37(d, 2H), 7.19(d, 2H), 7.12(d, 2H),6.92(m, 6H), 5.01(s, 2H), 4.97(s, 2H), 4.68(m, 1H), 4.59(m, 1H), 3.96(m,1H), 3.84(s, 3H), 3.82(s, 3H), 2.77(m, 2H).

4-Methoxybenzyl3-(4-(4-methoxybenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoate (76.4).Triethylamine (1 mL) was added to a mixture of 76.3 (1.89 g, 4.1 mmol),vinyl bromide (32.5 mL, 1.0 M solution in THF) and 1,4-phenylenediisocyanate (2.3 g, 14.35 mmol). The mixture was stirred at 80° C. for8 hours. After cooling, the solid was removed from the mixture byfiltration, and the filtrate was concentrated and purified by flashchromatography to give 76.4 (3 g). MS ESI (pos.) m/e: 474 (M+H). ¹HNMR(CDCl₃) δ 8.28(d, 1H), 7.37(d, 2H), 7.18(m, 4H), 6.92(m, 6H), 6.07(d,1H), 5.02(s, 2H), 4.97(s, 2H), 4.59(t, 1H), 3.84(s, 3H), 3.82(s, 3H),3.33(dd, 1H), 3.00(dd, 1H).

Ethyl 3-(4-hydroxyphenyl)-3-(isoxazol-3-yl)propanoate (76.5). TFA (10mL) was added to 76.4 (940 mg) in DCM (10 mL). The mixture was stirredat room temperature for 1.5 hours. TFA and DCM were removed undervacuum, and the residue was treated with EtOH (50 mL). The insolublesolid was removed by filtration. To the filtrate was added concentratedsulfuric acid (2 drops). The mixture was stirred at 80° C. overnight.After concentration, the crude product was purified by flashchromatography to give 76.5 (410 mg). MS ESI (pos.) m/e: 262 (M+H).¹HNMR (CDCl₃) δ 8.29(d, 1H), 7.12(d, 2H), 6.76(d, 2H), 6.10(d, 1H),4.56(t, 1H), 4.10(q, 2H), 3.27(dd, 1H), 2.97(dd, 1H), 1.19(t, 3H). Theracemic compound 76.5 was separated into two enantiomers 76.6 and 76.7using chiral preparative AD-H column (8% IPA/92% hexanes). Thestereochemistry of 76.6 and 76.7 was assigned arbitrarily.

(S)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (76). Cesium carbonate (14 mg, 0.042 mmol) was added into a mixtureof 76.6 (10 mg, 0.038 mmol) and6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (11mg, 0.038 mmol) in DMSO (0.5 mL). The mixture was stirred at roomtemperature for 2 hours and at 35° C. for 4 hours. After cooling, themixture was treated with EtOAc (5 mL) and brine (5 mL). The organiclayer was separated, washed with brine twice, dried and concentrated.The crude product was treated with THF (1 mL), MeOH (1 mL), water (0.5mL) and NaOH (0.05 mL, 10N). The mixture was stirred at room temperaturefor 4 hours. The organic solvent was blown away by nitrogen and theaqueous was acidified by HCl (0.18 mL, 3N). The aqueous was extractedwith DCM. The organic layer was dried, concentrated and purified byflash chromatography to give 76 (15 mg). MS ESI (pos.) m/e: 434 (M+H).¹HNMR (CDCl₃) δ 8.30(d, 1H), 7.35(m, 2H), 7.19(m, 3H), 6.96(d, 2H),6.09(d, 1H), 4.97(s, 2H), 4.57(t, 1H), 3.37(dd, 1H), 2.99(dd, 1H),1.71(s, 4H), 1.30(s, 12H).

6.89 Example 77

(R)-3-(Isoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (77). Compound 7 was synthesized using the procedure above forpreparing Example 76 using compound 76.7. MS ESI (pos.) m/e: 434 (M+H).¹HNMR (CDCl₃) δ 8.30(d, 1H), 7.35(m, 2H), 7.19(m, 3H), 6.96(d, 2H),6.09(d, 1H), 4.97(s, 2H), 4.57(t, 1H), 3.37(dd, 1H), 2.99(dd, 1H),1.71(s, 4H), 1.30(s, 12H).

6.90 Example 78

Synthesis of(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (78).

(2,3-Dihydro-1H-inden-5-yl)methanol (11) To a solution of 78.1 (1.0 g,6.17 mmol) in THF was slowly dripped BH₃.THF (30 mL, 1.0 M in THF) at 0°C. The reaction mixture was stirred at this temperature for 2 hours andthen quenched with water. The mixture was poured into water, andextracted with EtOAc. The crude product was chromatographed on a silicagel column to afford the alcohol 78.2. ¹HNMR (DMSO-d₆) δ 7.17-7.15 (m,2H), 7.05 (d, 1H, J=7.57 Hz), 5.04 (t, 1H, J=5.87 Hz), 4.45 (d, 2H,J=5.63 Hz), 2.84 (m, 4H), 2.01 (m, 2H).

(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (78) This compound was prepared by procedure analogous to thatdescribed in Example 109 starting with intermediate 78.2 which wasconverted to chloride 78.3 and then reacted with the imidazole phenolM12 shown in the reaction scheme and followed be removal of the estergroup. MS ESI (pos.) m/e: 377.2 (M+H). ¹HNMR (MeOH-d₄) δ 7.52-7.48 (d,2H), 7.26 (s, 1H), 7.23-7.15 (m, 4H), 7.02 (d, 2H, J=8.80 Hz), 5.04 (s,2H), 4.95 (m, 1H), 3.84 (s, 3H), 3.37 (m, 1H), 3.19 (m, 1H), 2.89 (t,4H, J=7.34 Hz), 2.08 (m, 2H).

6.91 Example 79

(R/S)-3-Pyrimidin-5-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (79). Compound 79.1 was prepared using the procedure in Method 12used to prepare M12.5 using pyrimidine-5-carboxaldehyde in place of1-methyl-2-imidazolecarboxaldehyde. Compound 79 was obtained fromcompound 79.1 by following the general Procedure E. MS ESI (neg.) M/E:443 (M−H). ¹HNMR (DMSO-d₆) δ 8.9 (s, 1H), 8.7 (s, 2H), 7.25 (m, 4H), 7.1(d, 1H), 6.8 (d, 1H), 4.9 (s, 2H), 4.3 (m, 1H), 3.1 (dd, 1H), 3.0 (dd,1H), 1.55 (s, 4H), 1.15 (s, 12H).

6.92 Example 80

Compound 80.1 was reduced to 80.2 using a procedure very similar to thatdescribed in JOC, 43, (1978), 2167. 80.2 was converted to 80.3 by simplytreating it with thionyl chloride at room temperature.

(S)-3-(i-Methyl-1H-imidazol-2-yl)-3-[4-(5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (80). Compound 80 was obtained from compound M12 and 80.3 byfollowing the general Procedure E. MS ESI (neg.) M/E: 389 (M−H). ¹HNMR(DMSO-d₆) δ 7.6 (s, 1H), 7.5 (s, 1H), 7.2 (d, 2H), 7.1-6.9 (overlappingsignals, 5H), 4.9 (s, 2H), 4.8 (m, 1H), 3.7 (s, 1H), 3.3 (dd, 1H), 3.0(dd, 1H).

6.93 Example 81

(S)-3-(1-Methyl-1H-tetrazol-5-yl)-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (81). Compound 81 was obtained from compound M14 by following thegeneral Procedure E. MS ESI (neg.) M/E: 447 (M−H). ¹HNMR (DMSO-d₆) δ 7.3(2s, 2H), 7.2 (d, 2H), 7.1 (d, 1H), 7.05 (d, 1H), 6.85 (d, 2H), 4.9 (s,2H), 4.6 (m, 1H), 3.8 (s, 3H), 3.2 (dd, 1H), 2.8 (dd, 1H), 1.55 (s, 4H),1.1 (s, 12H).

6.94 Example 82

(S)-3-Oxazol-2-yl-3-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylmethoxy)-phenyl]-propionicacid (82). Compound 82 was obtained from compound 82.1 (resolvedcompound of Method 11) by following the general Procedure E. MS ESI(neg.) M/E: 432 (M−H). ¹HNMR (MeOH-d₄) δ 7.8 (s, 1H), 7.3 (m, 2H), 7.2(m, 3H), 7.1 (s, 1H),6.95 (d, 2H), 5.0 (s, 2H), 4.6 (m, 1H), 3.8 (s,3H), 3.25 (dd, 1H), 2.9 (dd, 1H), 1.7 (s, 4H), 1.3 (s, 12H).

6.95 Examples 83 and 84

Synthesis of carboxylic acids(83) and (84).

Aldehyde (83.3). The benzyl bromide 83.1 (10.24 g, 32.5 mmol) and4-hydroxybenzaldehyde 83.2 (3.97 g, 32.5 mmol) were dissolved in 300 mLof acetone. K₂CO₃ (8.9 g, 65 mmol) was then added. After 18 hours atroom temperature, the reaction mixture was filtered through a plug ofsilica and concentrated afford 83.3 (11.4 g, 32 mmol, 98% yield). MS ESI(pos.) m/e: 357 (M+H)⁺.

Alcohol (83.5). 3-Mercapto-4-methyl-1,2,4-triazole (468 mg, 4.07 mmol)was dissolved in 100 mL of THF and the solution was cooled to −78° C.under a nitrogen atmosphere. 2.5 M n-BuLi (4.07 mL, 10.18 mmol) wasadded over one minute. After 5 minutes, a solution of aldehyde 83.3(1.45 g, 4.07 mmol) in 8 mL THF was added over 5 minutes. After 2 hours,the reaction mixture was poured onto 100 mL saturated NH4Cl(aq) solutionand subsequently diluted with 100 mL EtOAc. The organic layer was washedwith water (1×250 mL), brine (1×250 mL) and dried with MgSO₄. Theorganic layer was filtered and concentrated under reduced pressure. Thecrude material was flashed through silica with 40% EtOAc/Hex to afford83.5 (1.44 g, 3.06 mmol, 75% yield). MS ESI (pos.) m/e: 472 (M+H)⁺.

Alcohol (83.6). Alcohol 83.5 (1.44 g, 3.06 mmol) was dissolved in 50 mLof 4:1 THF/water. To this mixture was added NaNO₂ (422 mg, 6.12 mmol)followed by dropwise addition of concentrated HNO₃ (0.38 mL, 6.12 mmol).The reaction was stirred for 1 hour and then was diluted with 400 mL ofEtOAc. The organic layer was washed with NaHCO₃(aq) (2×150 mL), brine(1×150 mL), dried with MgSO₄, and filtered. The organic layer wasconcentrated under reduced pressure to afford 83.6 (1.34 g crudematerial). MS ESI m/e: 440 (M+H)⁺.

Ketone (83.7). Alcohol 83.6 (1.34 g crude) was dissolved in 50 mL of THFand Dess-Martin (15 mL, 0.3 M, 4.5 mmol) was added. After 18 hours, themixture was diluted with EtOAc and then washed with NaSO_(3(aq)) (2×150mL), brine (1×150 mL), and dried with MgSO₄ and filtered. The organiclayer was concentrated under reduced to afford ketone 83.7 (1.34 gcrude). MS ESI (pos.) m/e: 438 (M+H)⁺.

Ethyl ester (83.8). LHMDS (3 mL, 1 M, 3.00 mmol) was diluted with 25 mLof THF and cooled to −78° C. Then, ethyltrimethylsilylacetate (0.47 mL,2.57 mmol) was added dropwise and the mixture was allowed to warm to−50° C. over 1.5 hours. The mixture was cooled to −78° C. and the ketone83.7 (934 mg, 2.14 mmol) was added in 20 mL THF. After 1 hour, themixture was poured onto 100 mL saturated NH₄Cl(aq) solution andsubsequently diluted with 250 mL of EtOAc. The organic layer wasseparated and washed with brine (1×150 mL). The organic layer was driedwith MgSO4, filtered and concentrated under reduced pressure to afford83.8 as a crude material. MS ESI (pos.) m/e: 508 (M+H)+.

1,2,4-(4-Methyltriazole) (83.9). The ester 83.8 (˜2.14 mmol) wasdissolved in 50 mL of EtOAc then wet Pd/C (1.77 g) was added. Themixture was flushed with nitrogen, and a hydrogen balloon was attached.After 14 hours, the mixture was filtered through a small plug of silica,and the material was concentrated under reduced pressure. The residuewas prepared by HPLC C18 chromatography to afford phenol 83.9 (400 mg,1.45 mmol) as a white solid. The material was dissolved in MeOH and theenantiomers were separated on a Chiral AD-H column. 180 mg of eachenantiomer was obtained. MS ESI (pos.) m/e: 276 (M+H)+.

Carboxylic Acids (83 and 84). Benzyl bromide 83.10 (58 mg, 0.19 mmol)and phenol 83.9 (either of the separated enantiomers) (47 mg, 0.17 mmol)were dissolved in DMF (3 mL) and treated with Cs₂CO₃ (277 mg, 0.86mmol). The reaction was stirred at room temperature for 16 hours andthen diluted with EtOAc (50 mL) and washed with water (1×50 mL), brine(1×50 mL), then dried with MgSO₄, filtered, and concentrated to aresidue. The residue was dissolved in THF/MeOH/water, 3:1:1, and 10equivalents 2 N LiOH_((aq)) was added. The reaction was stirred for 12hours and then concentrated to a residue. The residue was purified byHPLC C18 column chromatography (ACN/Water/TFA). Eluent containingcompound 83 or 84 (depending on the enantiomer of 83.9 used) waslyophilized to afford a white solid (40 mg, 52%). ¹H NMR (500 mHz)(DMSO_(D6)) δ 8.50 (s, 1H); 7.35 (d, J=1.6 Hz, 1H); 7.32 (d, J=8.8 Hz,1H); 7.16-7.19 (m, 3H); 6.96 (d, J=9.4 Hz, 2H); 4.97 (s, 2H); 4.56 (dd,J=6.1, 9.4 Hz, 1H); 3.44 (s, 3H); 3.24 (dd, J=9.4, 17.2 Hz, 1H); 2.84(dd, J=6.1, 17.2 Hz, 1H); 1.64 (s, 4H); 1.24 (s, 6H); 1.23 (s, 6H). MSESI (pos.) m/e: 448.1 (M+H)⁺.

6.96 Example 85

Synthesis of3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (85).

4-Methoxybenzyl3-(4-(4-methoxybenzyloxy)phenyl)-3-(4,5-dihydroisoxazol-3-yl)propanoate(85.1). Ethylene was bubbled into a mixture of 76.3 (235 mg, 0.5 mmol,see Example 76) in benzene (2 mL) for 20 minutes. Phenyl isocyanate(0.22 mL, 2 mmol) and TEA (3 drops) were then added. The mixture wasstirred at room temperature for 2 days. The solid was removed byfiltration and washed by benzene. The filtrate was concentrated andpurified by flash chromatography to give 85.1 (200 mg). MS ESI (pos.)m/e: 476 (M+H). ¹HNMR (CDCl₃) δ 7.37(d, 2H), 7.21(d, 2H), 7.16(d, 2H),6.92(m, 6H), 5.05(dd, 2H), 4.98(s, 2H), 4.25(m, 2H), 4.10(t, 1H),3.84(s, 3H), 3.82(s, 3H), 3.24(dd, 1H), 2.79(m, 3H).

3-(4,5-Dihydroisoxazol-3-yl)-3-(4-hydroxyphenyl)propanoic acid (85.2).TFA (1 mL) was added to 85.1 (100 mg) in DCM (1 mL). The mixture wasstirred at room temperature for 40 hours. TFA and DCM were removed undervacuum, and the residue was treated with EtOH (50 mL). The insolublesolid was removed by filtration. The filtrate was concentrated to give85.2 (50 mg), which was used in the next step without furtherpurification. MS ESI (pos.) m/e: 236 (M+H).

3-(4,5-Dihydroisoxazol-3-yl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (85). Cesium carbonate (108 mg, 0.33 mmol) was added into a mixtureof 85.2 (25 mg, 0.11 mmol) and6-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (76mg, 0.27 mmol) in DMSO (1 mL). The mixture was stirred at 45° C. for 3hours. After cooling, the mixture was treated with EtOAc (5 mL) andbrine (5 mL). The organic layer was separated, washed with brine twice,dried and concentrated. The crude product was treated with THF (1 mL),MeOH (1 mL), water (0.5 mL) and NaOH (0.05 mL, 10N). The mixture wasstirred at room temperature for 4 hours. The organic solvent was blownaway by nitrogen, and the aqueous layer was acidified by HCl (0.18 mL,3N). The aqueous layer was extracted with DCM. The organic layer wasdried, concentrated and purified by flash chromatography to give 85 (15mg). MS ESI (pos.) m/e: 436 (M+H). ¹HNMR (CDCl₃) δ 7.35(m, 2H), 7.19(m,3H), 6.96(d, 2H), 4.97(s, 2H), 4.28(m, 2H), 4.07(t, 1H), 3.28(dd, 1H),2.79(m, 3H), 1.71(s, 4H), 1.30(s, 12H).

6.97 Example 86

Synthesis of(S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (86).

Starting material 86.1 was prepared according to the published procedureof Endo, Y. et al. (J. Med. Chem. 1998, 41, 1476-1496). To a solution of86.1 (150 mg, 0.78 mmol) in CHCl₃ (5 mL) was added SOCl₂ (3 mL). Thesolution was heated at reflux for 3 hours. The solvent and excess SOCl₂were removed under reduced pressure. The residue, crude 86.2 was pumpedto dryness for half an hour under vacuum and redissolved in DMF (5 mL).Cs₂CO₃ (1.3 g, 4 mmol), and the imidazole phenol M12 shown in thereaction scheme (0.21 g, 0.77 mmol) were added as shown in the reactionscheme. The reaction mixture was left to stir at room temperatureovernight, quenched with saline, extracted with EtOAc, andchromatographed on a silica gel column with 20-80% EtOAc/hexane toafford the ester 86.3.

(S)-3-(4-((8,8-Dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (86). The ester 86.3 was dissolved in THF (3 mL) and MeOH (3 mL).To the solution was added 2N NaOH aqueous (3 mL), and the reaction wasleft overnight. The mixture was neutralized with AcOH (0.5 mL),filtered, and directly purified with C₁₈ reverse-phase HPLC eluting with10-90% ACN/H₂O containing 0.1% TFA. The product fractions werelypholized to afford 86. MS ESI (pos.) m/e: 419.2 (M+H). ¹HNMR (MeOH-d₄)δ 7.52 (d, 2H, J=10.76 Hz), 7.37 (s, 1H), 7.22 (d, 2H, J=8.80 Hz), 7.09(d, 1H, J=7.83 Hz), 7.03 (d, 3H, J=8.56 Hz), 5.03 (s, 2H), 4.95 (m, 1H),3.84 (s, 3H), 3.37 (m, 1H), 3.19 (m, 1H), 2.76 (t, 2H, J=6.36 Hz), 1.82(m, 2H), 1.69 (m, 2H), 1.27 (s, 6H).

6.98 Example 87

Synthesis of(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (87).

1-(5,5,8,8-Tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethanol (87.2)To a solution of 87.1 (1.0 g, 4.34 mmol) in MeOH (20 mL) was added NaBH₄(0.41 g, 10.8 mmol) at 0° C. The reaction was left at room temperatureovernight. The solvent was then removed under reduced pressure. Theresidue was extracted with EtOAc/H₂O. The crude product waschromatographed with 0-20% EtOAc/hexane to afford 87.2. ¹HNMR (DMSO-d₆)δ 7.26 (d, 1H), 7.24 (d, 1H), 7.06 (dd, 1H), 4.99 (d, 1H), 4.64 (m, 1H),1.64 (s, 4H), 1.29 (d, 3H), 1.24 (m, 12H).

(3S)-3-(1-Methyl-1H-imidazol-2-yl)-3-(4-(1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)ethoxy)phenyl)propanoicacid (87) To a mixture of compound the imidazole phenol compound M12shown in the reaction scheme (200 mg, 0.73 mmol), 87.2 (370 mg, 1.59mmol), and tributylphosphine (0.54 mL, 2.19 mmol) in THF (8 mL) wasadded N,N,N′,N′-tetramethylazodicarboxamide(TMAD) (0.38 g, 2.21 mmol)after bubbling with Ar for 2 minutes. The reaction mixture was stirredat room temperature overnight, quenched with saline, extracted withEtOAc, and chromatographed on a silica gel column to afford the ester87.3. The ester was hydrolyzed by procedure analogous to that describedfor Example 86. MS ESI (pos.) m/e: 461.2 (M+H). ¹HNMR (MeOH-d₄) δ7.50-7.46 (m, 2H), 7.29-7.26 (m, 2H), 7.14-7.10 (m, 3H), 6.91 (d, 2H,J=8.81 Hz), 5.34 (m, 1H), 4.90 (m, 1H), 3.81 (ss, 3H), 3.31 (m, 1H),3.16 (m, 1H), 1.69 (s, 4H), 1.58 (d, 3H, J=6.35 Hz), 1.31 (m, 1H),1.27-1.16 (m, 12H).

6.99 Example 88

Synthesis of(S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (88).

6-(Bromomethyl)-4,4-diethyl-1,1-dimethyl-1,2,3,4-tetrahydronaphthalene(88.2) Starting material 88.1 was prepared according to the publishedprocedure of Kim, C. et al. (Tetrahedron. Lett. 1994, 35 (19),3017-3020). A mixture of 88.1 (0.5 g, 2.17 mmol), NBS (0.58 g, 3.25mmol), and dibenzoyl peroxide (53 mg) in CCl₄ (10 mL) was heated atreflux for 5 hours. The reaction was cooled, and the precipitate wasfiltered out. The solvent was removed providing crude 88.2, which wasused directly in the next step.

(S)-3-(4-((8,8-Diethyl-5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (88) Compound 88 was prepared using a procedure analogous to thatdescribed in Example 86 starting with the imidazole phenol compound M12shown in the reaction scheme and 88.2. MS ESI (pos.) m/e: 475.1 (M+H).¹HNMR (MeOH-d₄) δ 7.47 (dd, 2H, J=11.7, 2.2 Hz), 7.32 (d, 1H, J=8.1 Hz),7.09-7.20 (m, 4H), 7.01-6.94 (m, 2H), 5.03 (s, 2H), 4.95-4.88 (m, 1H),3.83 (s, 3H), 3.34 (m, 1H), 3.14 (m, 1H), 1.73-1.52 (m, 6H), 1.59-1.47(m, 2H), 1.24 (s, 6H), 0.68 (t, 6H, J=7.3 Hz).

6.100 Example 89

Synthesis of(S)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (89).

Compound 89.1 was prepared using the procedure of Example 45.2 set forthin US 2006/0004012 which is hereby incorporated by reference. 89.2 and89.3 were separated from racemic material 89.1 using a prep chiral ADcolumn using 10% i-PrOH in hexane as eluent. Both compounds (R)-ethyl3-(4-fluorophenyl)-3-(4-hydroxyphenyl)propanoate 89.2 (the first peak onAD column, shorter retention time) and (S)-ethyl3-(4-fluorophenyl)-3-(4-hydroxyphenyl)propanoate 89.3 (the second peakon AD column, longer retention time) were obtained as white solid.

(S)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (89). Compound 89 was obtained from compound 89.3 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 459 (M−H). ¹HNMR (500 MHz,CDCl₃, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J=10Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, 1H J=10 Hz), 3.06 (ddd,2H, J=5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32(s, 6H), 1.31(s, 6H).

6.101 Example 90

Synthesis of(R)-3-(4-fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (90).

(R)-3-(4-Fluorophenyl)-3-(4-((5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoicacid (90). Compound 90 was obtained from compound 89.2 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 459 (M−H). ¹HNMR (500 MHz,CDCl₃, ppm) δ 7.35-7.37 (m, 2H), 7.19-7.23 (m, 3H), 7.16 (d, 2H, J=10Hz), 6.94-7.02 (m, 4H), 4.98 (s, 2H), 4.50 (t, 1H J=10 Hz), 3.06 (ddd,2H, J=5 Hz, 10 Hz, 10 Hz), 1.72 (s, 4H), 1.32(s, 6H), 1.31(s, 6H).

6.102 Example 91

Synthesis of(S)-3-(4-((3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (91).

6-Bromo-7-(bromomethyl)-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene(91.2). The mixture of6-bromo-7-methyl-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (4.20g, 15 mmol), NBS (3.20 g, 18 mmol), 2,2′-azobisisobutyronitrile (0.3 g,1.8 mmol) and CCl₄ (120 mL) was heated at reflux for 16 hours. Themixture was concentrated under reduced pressure to about 50 mL. Thereaction was then filtered, and the solid was washed with Et₂O (20 mL).The combined organic solution was then concentrated under vacuum togenerate crude product. Crude 91.2 was generated as a brown oil and useddirectly in the next step without further purification.

(S)-3-(4-((3-Bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (91). Compound 91.3 was obtained from compound M12 and 91.2following the general procedure E and isolated as a generalintermediate. Compound 91 was obtained from compound 91.3 by followingthe general procedure E. LC-MS ESI (neg.) M/E: 523 (M−H). ¹HNMR (500MHz, MeOH-d₄, ppm) δ 7.52 (s, 1H), 7.43 (s, 1H), 7.18-7.21 (m, 4H),6.96-7.20 (m, 2H), 5.07 (s, 2H), 4.73 (dd, 1H J=5 Hz, 10 Hz), 3.65 (s,3H), 3.27 (dd, 1H, J=5 Hz, 10 Hz), 2.98 (dd, 1H, J=5 Hz, 10 Hz), 1.70(s, 4H), 1.28(s, 6H), 1.22(s, 6H).

6.103 Example 92

Synthesis of(S)-3-(4-((3-cyclopropyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (92).

(S)-Ethyl3-(1-methyl-1H-imidazol-2-yl)-3-(4-((3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)propanoate(92.1). The mixture of compound 91 (166 mg, 0.3 mmol), cyclopropylboronic acid (129 mg, 1.5 mmol), K₃PO₄ (212 mg, 1 mmol), Pd(OAc)₂ (26mg, 0.12 mmol), Sphos (100 mg, 0.24 mmol) and dioxane (3 mL) was purgedwith nitrogen, and then heated at 100° C. overnight. The reactionmixture was directly purified by CombiFlash. The compound 92.1 wasgenerated as a colorless oil. LC-MS ESI (pos.) M/E: 515 (M+H).

(S)-3-(4-((3-Cyclopopyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (92). Compound 92 was obtained from compound 92.1 by following thegeneral procedure E. LC-MS ESI (neg.) M/E: 485 (M−H). ¹HNMR (500 MHz,MeOH-d₄, ppm) δ 7.53 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.23-7.25 (m,2H), 7.05-7.07 (m, 2H), 7.01 (s, 1H), 5.22 (s, 2H), 4.97 (dd, 1H J=5 Hz,10 Hz), 3.85 (s, 3H), 3.26 (dd, 1H, J=10 Hz, 15 Hz), 3.19 (dd, 1H, J=10Hz, 20 Hz), 1.96 (m, 1H), 1.69 (s, 4H), 1.26(s, 6H), 1.23(s, 6H),0.87-0.90 (m, 2H), 0.62-0.65 (m, 2H).

6.104 Example 93

Synthesis of(S)-3-(4-((3-methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (93).

(S)-3-(4-((3-Methyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (93). Compound 93 was obtained from compound 91 and methyl boronicacid by following the same procedure used for compound 92. LC-MS ESI(neg.) M/E: 459 (M−H). ¹HNMR (500 MHz, MeOH-d₄, ppm) δ 7.53 (s, 1H),7.51 (s, 1H), 7.27 (s, 1H), 7.22-7.24 (m, 2H), 7.15 (s, 1H), 7.04-7.07(m, 2H), 5.03 (s, 2H), 4.97 (dd, 1H J=5 Hz, 10 Hz), 3.85 (s, 3H), 3.36(dd, 1H, J=10 Hz, 20 Hz), 3.19 (dd, 1H, J=10 Hz, 20 Hz), 2.30 (s, 3H),1.70 (s, 4H), 1.28(s, 6H), 1.24(s, 6H).

6.105 Example 94

Synthesis of(S)-3-(4-((3-ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (94).

(S)-3-(4-((3-Ethyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)methoxy)phenyl)-3-(1-methyl-1H-imidazol-2-yl)propanoicacid (94). Compound 94 was obtained from compound 91 and ethyl boronicacid by following the same procedure as used for compound 92. LC-MS ESI(neg.) M/E: 473 (M−H). ¹HNMR (500 MHz, MeOH-d4, ppm) δ 7.53 (s, 1H),7.51 (s, 1H), 7.29 (s, 1H), 7.22-7.26 (m, 2H), 7.19 (s, 1H), 7.03-7.07(m, 2H), 5.05 (s, 2H), 4.97 (dd, 1H J=5 Hz, 10 Hz), 3.86 (s, 3H), 3.36(dd, 1H, J=10 Hz, 15 Hz), 3.20 (dd, 1H, J=10 Hz, 20 Hz), 2.66 (q, 2H,J=10 Hz), 1.71 (s, 4H), 1.29 (s, 6H), 1.25 (s, 6H), 1.22 (t, 3H, J=10Hz).

6.106 Cell-based Aequorin Assay

Cell-based aequorin assays were employed to characterize the modulatoryactivity of compounds on the GPR40 signaling pathway. In an exemplaryassay, CHO cells were stably transfected with both GPR40 and Aequorin(Euroscreen). Cells were detached from the tissue culture dish with 2 mLof trypsin (0.25% (w/v)). Trypsinization was halted with 28 mL of HanksBuffered Salt Solution containing 20 mM Hepes (H/HBSS) and 0.01% fattyacid-free human serum albumin (HSA). Coelantrazine is added to 1 ug/mL,and the cells were incubated for 2 hours at room temperature. Compoundswere dissolved in DMSO for preparation of 10 mM stock solutions.Compounds were diluted in H/HBSS containing 0.01% HSA. Serial dilutionsof the test compounds were prepared to determine dose response.

Aequorin luminescence measurements were made using an EG&G Berthold96-well luminometer, and the response was measured over a 20 secondinterval after cells and compounds were mixed. The maximum relativelight units was plotted to determine dose response. The EC₅₀ (effectiveconcentration to reach 50% maximal response) was determined from thedose response plot.

Table 1 presents representative data (EC₅₀ values) obtained forexemplary compounds of the invention for the relative activation ofhuman GPR40.

The stereoisomers in Table 1 are as specified, i.e., S-enantiomers orR-enantiomers, and if not specified, or if shown with wavy bonds, aremixtures of S-enantiomers and R-enantiomers. In addition, the presentinvention provides the S-enantiomers, the R-enantiomers, and mixtures ofboth S-enantiomers and R-enantiomers including racemates of eachcompound prepared according to the synthetic methods described herein oradapted with the necessary minor modifications from these methods.

6.107 Insulin Secretion Assay

Human islets were isolated from cadaveric donors. Islets were treatedwith trypsin (0.25% (w/v) and cells were seeded in 96-well platescontaining 3,000 cells per well. Cells were cultured in Roswell ParkMemorial Institute (RMPI) media containing 10% fetal bovine serum.

For determination of insulin secretion, media was removed from isletcells and replaced with Krebs-Ringer bicarbonate buffer containing 10 mMHEPES (KRBH) and 2 mM glucose. After one hour incubation, media wasreplaced with KRBH containing 11.2 mM glucose and test compounds.Insulin released into the medium from the islet cells was measured usingscintillation proximity assay (SPA). The compounds of Examples 4 and 9stimulated insulin secretion from islet cells with EC₅₀ values of lessthan 1 uM.

For determination of insulin secretion from rodent islets, C57/Bl6 miceare euthanized with carbon dioxide gas. The pancreatic bile duct isclamped proximal to the duodenum and then cannulated. H/HBSS containing0.75 mg/mL collagenase XI (Sigma) is then infused into the pancreasthrough the cannula. The pancreas is excised and then incubated at 37°C. for 13 minutes to complete enzymatic digestion. The collagenasedigestion is quenched in H/HBSS containing 1% BSA and washed once in thesame buffer. Islets can be purified using density gradientcentrifugation using Histopaque (Sigma) and are hand-picked under astereomicroscope.

Islets are cultured overnight in Roswell Park Memorial Institute (RMPI)media containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol.Following overnight culture, islets are incubated in KRBH containing 2.8mM glucose for one hour.

For determination of insulin secretion, islets are incubated in DMEMcontaining 12.5 mM glucose and test compounds for one hour. Insulinreleased into the culture medium from the islets is measured using aninsulin ELISA. TABLE 1 Aequorin Assay Using Human GPR40 Relative No.Structure^(a) EC₅₀ ^(b) 1

++++ 2

++++ 3

++++ 4

++++ 5

++++ 6

++++ 7

++++ 8

++++ 9

++ 10

++++ 11

++++ 12

++++ 14

++++ 15

+++++ 16

++++ 17

++++ 18

++++ 19

++ 20

+++ 21

++++ 23

++ 24

++++ 25

++++ 26

+++ 27

++++ 29

+++ 31

++ 32

++ 33

++ 34

++ 36

+++ 37

+++ 38

+++ 39

++ 41

+++ 42

+++ 44

++++ 45

++++ 46

++++ 47

+++ 48

+++ 49

++ 50

++++ 51

+++ 53

+++ 54

++++ 55

+++ 56

++ 57

+++ 58

++ 59

+ 60

+ 61

+ 62

+ 63

+ 64

+ 65

+ 66

+ 67

+ 68

++ 69

+++ 70

+++ 71

+++ 72

+++ 73

++++ 74

+++ 75

+++ 76

++++ 77

++ 78

++ 79

++ 80

+++ 81

++++ 82

++++ 83

+ 84

+++ 85

+++ 86

+++ 87

+ 88

+++ 89

+++ 90

++ 91

+++ 92

+ 93

+++ 94

+++^(a)When present, the “

” bond indicates a mixture of stereoisomers are present in the exemplarycompound.^(b)EC₅₀ Ranges:+ EC₅₀ > 10 μM++ 1 μM = EC₅₀ = 10 μM+++ 0.1 μM = EC₅₀ < 1 μM++++ 0.01 μM = EC₅₀ < 0.1 μM+++++ EC₅₀ < 0.01 μM^(c)Aeguorin assay data from transiently transfected cell line.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically and individually indicated to beincorporated by reference. Each publication and patent application citedherein is incorporated in its entirety as if fully set forth herein.Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

1. A compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, wherein Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; L¹ is a bond, (C₁-C₄)alkylene,(C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C4)alkylene-N(R^(b))SO₂, or C(O)N(R^(b));

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring;L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂; M is anaromatic ring, a heteroaromatic ring, (C₅-C₈)cycloalkylene,aryl(C₁-C₄)alkylene, or heteroaryl(C₁-C₄)alkylene; X is CR¹R^(1′),N(R^(1″)), O, or S(O)_(k); L³ is a (C₁-C₅)alkylene or(C₂-C₅)heteroalkylene; A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂,—SO₂NH₂, —C(O)NHSO₂CH₃, —CHO, thiazolidinedionyl, hydroxyphenyl, orpyridyl; R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃) alkyl, or(C₂-C₆)heteroalkyl; R^(b) is hydrogen, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³; R^(1′) ishydrogen, cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl; R² and R³ areindependently selected from hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl;optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached comprisingfrom 0 to 2 additional heteroatoms selected from N, O, or S; and thesubscript k is 0, 1, or 2
 2. The compound of claim 1, wherein L¹ is abond, Q is H or aryl,

represents a substituted benzo-fused (C₅-C₈)cycloalkane ring or anunsubstituted benzo-fused (C₅-C₈)cycloalkane ring, L² is O,oxymethylene, or oxyethylene, M is benzene and X is para to L², X isCR¹R^(1′), R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³, R^(1′) isH, L³ is methylene, and A is CO₂H, or a pharmaceutically acceptablesalt, solvate, stereoisomer, or prodrug thereof.
 3. The compound ofclaim 2, wherein the compound is a pharmaceutically acceptable salt orsolvate.
 4. The compound of claim 2, wherein the compound is a prodrug.5. The compound of claim 4, wherein the prodrug is an ester.
 6. Thecompound of claim 1, wherein the compound has the formula (II):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein Q is selected from hydrogen, aryl, or heteroaryl;

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring;L² is selected from O or S(O)_(k); R¹ is selected from (C₂-C₈)alkynyl,aryl, heteroaryl, or —C(O)NR²R³; R² and R³ are independently selectedfrom hydrogen or (C₁-C₄)alkyl; R⁴ is independently selected fromsubstituted (C₁-C₆)alkyl, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,halogen, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, or —NO₂, wherein R′, R″ and R′″ are each independentlyselected from hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl,unsubstituted aryl, aryl substituted with one to three halogens,unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, oraryl-(C₁-C₄)alkyl groups; R⁵ is independently selected from(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; the subscript kis 0, 1 or 2; the subscript n is 0, 1 or 2; and the subscript p is 0, 1,2, 3 or
 4. 7. The compound of claim 6, wherein R⁴ is independentlyselected from (C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro. 8.The compound of claim 6, wherein the compound has the formula (IIIa) or(IIIb):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof. 9.The compound of claim 6, wherein

is a benzo-fused (C₅-C₈)cycloalkane ring selected from dihydroindene,tetrahydronaphthalene, tetrahydrobenzo[7]annulene, orhexahydrobenzo[8]annulene.
 10. The compound of claim 6, wherein thecompound has the formula (IV):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein the subscript m is 1, 2, 3 or
 4. 11. The compound ofclaim 10, wherein the subscript m is 1 or
 2. 12. The compound of claim10, wherein Q is hydrogen; L² is oxygen; the subscript n is 1 or 2; R⁴is independently selected from methyl, halogen, or (C₁-C₆)alkoxy; and R¹is (C₂-C₃)alkynyl.
 13. The compound of claim 6, wherein the compound hasthe formula (VII):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof.
 14. The compound of claim 2, wherein R¹ is selected fromprop-1-ynyl, imidazolyl, oxazolyl, phenyl, pyrazolyl, tetrazolyl,thiazolyl, thiophenyl, triazolyl, or —C(O)NR²R³.
 15. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier, diluent,or excipient, and the compound of claim
 1. 16. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier, diluent,or excipient, and the compound of claim
 2. 17. A method for treating adisease or condition, comprising: administering to a subject in needthereof, a therapeutically effective amount of the compound of claim 1,wherein the disease or condition is selected from the group consistingof type II diabetes, obesity, hyperglycemia, glucose intolerance,insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer, and edema.
 18. The method of claim 17, wherein the disease orcondition is type II diabetes.
 19. A method for treating a disease orcondition, comprising: administering to a subject in need thereof, atherapeutically effective amount of the compound of claim 1, wherein thedisease or condition is a disease or condition responsive to themodulation of GPR40.
 20. The method of claim 19, wherein the disease orcondition is selected from the group consisting of type II diabetes,obesity, hyperglycemia, glucose intolerance, insulin resistance,hyperinsulinemia, hypercholesterolemia, hypertension,hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia,dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease,atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders,nephropathy, diabetic neuropathy, diabetic retinopathy, sexualdysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer, and edema.21. The method of claim 19, wherein the compound is administered orally,parenterally, or topically.
 22. The method of claim 21, wherein thecompound is administered in combination with a second therapeutic agent.23. The method of claim 22, wherein the second therapeutic agent ismetformin or is a thiazolidinedione.
 24. A method for modulating GPR40function in a cell, comprising: contacting the cell with the compound ofclaim
 1. 25. A method for modulating GPR40 function, comprising:contacting GPR40 with the compound of claim
 1. 26. A method formodulating circulating insulin concentration in a subject, comprising:administering the compound of claim 1 to the subject.
 27. The method ofclaim 26, wherein the circulating insulin concentration is increased inthe subject after the compound is administered to the subject.
 28. Themethod of claim 26, wherein the circulating insulin concentration isdecreased in the subject after the compound is administered to thesubject.
 29. A therapeutic composition, comprising; the compound ofclaim 1 and a second therapeutic agent as a combined preparation forsimultaneous, separate, or sequential use in the treatment of a diseaseor condition mediated by GPR40.
 30. The therapeutic composition of claim29, wherein the second therapeutic agent is selected from metformin or athiazolidinedione.
 31. A compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, wherein Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; L¹ is a bond, (C₁-C₄)alkylene,(C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene-SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b));

represents a cyclohexane ring or a benzo-fused (C₅-C₈)cycloalkane ring;L² is a bond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O,S(O)_(k), N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)),(C₁-C₄)alkylene-C(O)N(R^(b)), (C₁-C₄)alkylene-N(R^(b))C(O),(C₂-C₄)alkenylene-C(O)N(R^(b)), (C₂-C₄)alkenylene-N(R^(b))C(O),(C₁-C₄)alkylene-SO₂N(R^(b)), (C₁-C₄)alkylene-N(R^(b))SO₂,(C₂-C₄)alkenylene-SO₂N(R^(b)), or (C₂-C₄)alkenylene-N(R^(b))SO₂; M is abenzene ring, and R¹ is combined with M to form a 5-, 6-, or 7-memberedbenzo-fused cycloalkane ring comprising 0, 1, or 2 heteroatoms selectedfrom N, O, and S; X is CR¹R^(1′); L³ is a bond, (C₁-C₅)alkylene or(C₂-C₅)heteroalkylene; A is —CO₂H, tetrazol-5-yl, —SO₃H, —PO₃H₂,—SO₂NH₂, —C(O)NHSO₂CH₃, —CHO, thiazolidinedion-yl, hydroxyphenyl, orpyridyl; R^(a) is hydrogen, (C₁-C₆)alkyl, aryl(C₁-C₃) alkyl, or(C₂-C₆)heteroalkyl; R^(b) is hydrogen, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; R^(1′) is hydrogen, cyano, aryl, heteroaryl,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, or (C₂-C₈)alkynyl; R^(1″) is hydrogen,aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or(C₃-C₈)cycloalkyl; and the subscript k is 0, 1 or
 2. 32. The compound ofclaim 31, wherein Q is hydrogen, aryl, or heteroaryl; L¹ is a bond; L²is O or S(O)_(k); L³ is a (C₁-C₃)alkylene; and A is —CO₂H.
 33. Thecompound of claim 31, wherein M is combined with R¹ to form abenzo-fused cycloalkane ring having a formula selected from the groupconsisting of:

wherein, the dotted lines indicate sites of attachment to L² and L³. 34.The compound of claim 31, wherein M-X-L³-A is selected from the groupconsisting of:

wherein the dotted line indicates the site of attachment to L².
 35. Thecompound of claim 31, wherein the compound has the formula (VIII) or(IX)

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, wherein: Q is selected from hydrogen, aryl, or heteroaryl; L²is selected from O or S(O)_(k); R⁴ is independently selected from(C₁-C₆)alkyl, halogen, (C₁-C₆)alkoxy, cyano, or nitro; the subscript mis 1, 2, 3 or 4; and the subscript n is 0, 1 or
 2. 36. A pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier, diluent,or excipient, and the compound of claim
 31. 37. A method for treating adisease or condition, comprising: administering to a subject in needthereof, a therapeutically effective amount of the compound of claim 31,wherein the disease or condition is selected from the group consistingof type II diabetes, obesity, hyperglycemia, glucose intolerance,insulin resistance, hyperinsulinemia, hypercholesterolemia,hypertension, hyperlipoproteinemia, hyperlipidemia,hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X,cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis,thrombotic disorders, nephropathy, diabetic neuropathy, diabeticretinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia,cancer, and edema.
 38. The method of claim 37, wherein the disease orcondition is type II diabetes.
 39. The method of claim 37, wherein thecompound is administered in combination with a second therapeutic agent.40. The method of claim 39, wherein the second therapeutic agent ismetformin or is a thiazolidinedione.
 41. A method for modulatingcirculating insulin concentration in a subject, comprising:administering the compound of claim 31 to the subject.
 42. A therapeuticcomposition, comprising; the compound of claim 31 and a secondtherapeutic agent as a combined preparation for simultaneous, separate,or sequential use in the treatment of a disease or condition mediated byGPR40.
 43. The therapeutic composition of claim 42, wherein the secondtherapeutic agent is selected from metformin or a thiazolidinedione. 44.A compound having the formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrugthereof, wherein Q is hydrogen, aryl, heteroaryl, (C₁-C₆)alkyl, or(C₂-C₆)heteroalkyl; L¹ is a bond, (C₁-C₄)alkylene,(C₂-C₄)heteroalkylene, O, S(O)_(k), N(R^(a)),C(O)—(C₅-C₇)heterocycloalkylene, (C₁-C₄)alkylene—SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, or C(O)N(R^(b));

represents an optionally substituted (C₅-C₈)cycloalkane ring; L² is abond, (C₁-C₆)alkylene, (C₂-C₆)heteroalkylene, oxymethylene, O, S(O)_(k),N(R^(a)), C(O)N(R^(b)), SO₂N(R^(b)), (C₁-C₄)alkylene-C(O)N(R^(b)),(C₁-C₄)alkylene-N(R^(b))C(O), (C₂-C₄)alkenylene-C(O)N(R^(b)),(C₂-C₄)alkenylene-N(R^(b))C(O), (C₁-C₄)alkylene—SO₂N(R^(b)),(C₁-C₄)alkylene-N(R^(b))SO₂, (C₂-C₄)alkenylene—SO₂N(R^(b)), or(C₂-C₄)alkenylene-N(R^(b))SO₂; M is an aromatic ring, a heteroaromaticring, (C₅-C₈)cycloalkylene, aryl(C₁-C₄)alkylene, orheteroaryl(C₁-C₄)alkylene; X is CR¹R^(1′), N(R^(1″)), O, or S(O)_(k); L³is a bond, (C₁-C₅)alkylene, or (C₂-C₅)heteroalkylene; A is —CO₂H,tetrazol-5-yl, —SO₃H, —PO₃H₂, —SO₂NH₂, —C(O)NHSO₂CH₃, —CHO,thiazolidinedion-yl, hydroxyphenyl, or pyridyl; R^(a) is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₃) alkyl, or (C₂-C₆)heteroalkyl; R^(b) ishydrogen, (C₁-C₆)alkyl, or (C₂-C₆)heteroalkyl; R¹ is cyano, aryl,heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)alkenyl,(C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³; R^(1′) is hydrogen,cyano, aryl, heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl; R^(1″) is hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, or (C₃-C₈)cycloalkyl; R² and R³ areindependently selected from hydrogen, aryl, heteroaryl, (C₁-C₈)alkyl,(C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or (C₃-C₈)heterocycloalkyl;optionally, R² and R³ are combined to form a 4-, 5-, 6- or 7-memberedring containing the nitrogen atom to which they are attached comprisingfrom 0 to 2 additional heteroatoms selected from N, O, or S; and thesubscript k is 0, 1, or 2
 45. The compound of claim 44, wherein L¹ is abond, Q is H or aryl,

represents an optionally substituted cyclopentane or cyclohexane ring,L² is O, oxymethylene, or oxyethylene, M is benzene and X is para to L²,X is CR¹R^(1′), R¹ is cyano, aryl, heteroaryl, (C₂-C₈)alkenyl,(C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, or —C(O)NR²R³, R^(1′) isH, L³ is methylene, and A is CO₂H or a pharmaceutically acceptable salt,solvate, stereoisomer, or prodrug thereof.
 46. The compound of claim 45,wherein the compound is a pharmaceutically acceptable salt or solvate.47. The compound of claim 44, wherein the compound has the formula (II):

or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrugthereof, wherein Q is selected from hydrogen, aryl, or heteroaryl;

represents a cycloalkane ring; L² is selected from O or S(O)_(k); R¹ isselected from (C₂-C₈)alkynyl, aryl, heteroaryl, or —C(O)NR²R³;optionally, R¹ is combined with the adjacent benzene ring to form a 5-,6- or 7-membered benzo-fused cycloalkane ring containing 0, 1 or 2heteroatoms selected from N, O or S; R² and R³ are independentlyselected from hydrogen or (C₁-C₄)alkyl; R⁴ is independently selectedfrom the group consisting of substituted (C₁-C₆)alkyl, —R′, ═O, —OR′,═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″,—NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″,—S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, and —NO₂, where R′, R″ andR′″ are each independently selected from hydrogen, unsubstituted(C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl, aryl substituted withone to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups,halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ is independentlyselected from the group consisting of (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or nitro; the subscript k is 0, 1 or 2; thesubscript n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14; andthe subscript p is 0, 1, 2, 3 or
 4. 48. The compound of claim 47,wherein R⁴ is independently selected from (C₁-C₆)alkyl, halogen,(C₁-C₆)alkoxy, cyano, or nitro.
 49. The compound of claim 47, whereinthe compound has having the formula (IIIa) or (IIIb):

or a pharmaceutically acceptable salt, solvate, or prodrug thereof,wherein R¹ is (C₂-C₈)alkynyl, aryl, heteroaryl, or —C(O)NR²R.
 50. Apharmaceutical composition, comprising: a pharmaceutically acceptablecarrier, diluent, or excipient, and the compound of claim
 44. 51. Amethod for treating a disease or condition, comprising: administering toa subject in need thereof, a therapeutically effective amount of thecompound of claim 44, wherein the disease or condition is selected fromthe group consisting of type II diabetes, obesity, hyperglycemia,glucose intolerance, insulin resistance, hyperinsulinemia,hypercholesterolemia, hypertension, hyperlipoproteinemia,hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome,syndrome X, cardiovascular disease, atherosclerosis, kidney disease,ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy,diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia,hypoglycemia, cancer, and edema.
 52. The method of claim 51, wherein thedisease or condition is type II diabetes.
 53. The method of claim 51,wherein the compound is administered in combination with a secondtherapeutic agent.
 54. The method of claim 53, wherein the secondtherapeutic agent is metformin or is a thiazolidinedione.
 55. A methodfor modulating circulating insulin concentration in a subject,comprising: administering the compound of claim 44 to the subject.
 56. Atherapeutic composition, comprising; the compound of claim 44 and asecond therapeutic agent as a combined preparation for simultaneous,separate, or sequential use in the treatment of a disease or conditionmediated by GPR40.
 57. The therapeutic composition of claim 56, whereinthe second therapeutic agent is selected from metformin or athiazolidinedione.
 58. A method of synthesizing a compound of formulaXXIV, the compound of formula XXIV having the following structure:

the method comprising: (a) reacting a compound of formula XXII with acompound of formula XXIII to produce the compound of formula XXIV,wherein the compounds of formula XXII and XXIII have the followingstructures:

wherein, Alk is a straight or branched chain alkyl group having from 1to 8 carbon atoms; R¹ is selected from cyano, aryl, heteroaryl,(C₂-C₈)alkenyl, (C₃-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)alkynyl, orC(O)NR²R³; R² and R³ are independently selected from hydrogen, aryl,heteroaryl, (C₁-C₈)alkyl, (C₂-C₈)heteroalkyl, (C₃-C₈)cycloalkyl, or(C₃-C₈)heterocycloalkyl; or optionally, R² and R³ are combined to form a4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which theyare attached comprising from 0 to 2 additional heteroatoms selected fromN, O, or S; R⁴ is independently selected from substituted (C₁-C₆)alkyl,—R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″,—NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH, —NR′C(NH₂)═NH, —NH—C(NH₂)═NR′,—SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″, —NR″SO₂R, —CN, or —NO₂, whereinR′, R″ and R′″ are each independently selected from hydrogen,unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstituted aryl, arylsubstituted with one to three halogens, unsubstituted alkyl, alkoxy orthioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkyl groups; R⁵ isindependently selected from the group consisting of (C₁-C₆)alkyl,halogen, (C₁-C₆)alkoxy, cyano, or nitro; m is 1, 2, 3, or 4; n is 0, 1,or 2; p is 0, 1, 2, 3, or 4; Y is selected from substituted(C₁-C₆)alkyl, —R′, ═O, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, halogen,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR′—SO₂NR″R′″, —NR″CO₂R′, —NH—C(NH₂)═NH,—NR′C(NH₂)═NH, —NH—C(NH₂)═NR′, —SiR′R″R′″, —S(O)R′, —SO₂R′, —SO₂NR′R″,—NR″SO₂R, —CN, and —NO₂, where R′, R″ and R′″ each independently referto hydrogen, unsubstituted (C₁-C₈)alkyl or heteroalkyl, unsubstitutedaryl, aryl substituted with one to three halogens, unsubstituted alkyl,alkoxy or thioalkoxy groups, halo(C₁-C₄)alkyl, or aryl-(C₁-C₄)alkylgroup; W is a leaving group; and further wherein, the compounds offormula XXII and XXIV can be a mixture of compounds having the R and Sstereochemistry at the carbon bonded to R¹, can have the Rstereochemistry at the carbon bonded to R¹, or can have the Sstereochemistry at the carbon bonded to R¹.
 59. The method of claim 58,wherein W is selected from OH, a halogen, a group of formula OTs, OMs,or OTf, wherein Ts is p-toluenesulfonyl, Ms is methanesulfonyl, and Tfis trifluoromethanesulfonyl.
 60. The method of claim 58, wherein Alk ismethyl or ethyl.
 61. The method of claim 58, wherein m is 1 or
 2. 62.The method of claim 58, wherein W is OH, and a phosphine selected from atrialkylphosphine, a dialkylarylphosphine, an alkyldiarylphosphine, or atriarylphosphine and an azodicarboxylate are used to react the compoundof formula XXII with the compound of formula XXIII.
 63. The method ofclaim 58, wherein W is a halogen selected from Br or Cl, and a base isused to react the compound of formula XXII with the compound of formulaXXIII.
 64. The method of claim 58, wherein n is
 0. 65. The method ofclaim 58, wherein p is
 0. 66. The method of claims 58, wherein Y is ahalogen, and the method further comprises reacting the compound offormula XXIV with a boronic acid compound.
 67. The method of claim 66,wherein the boronic acid comprises a compound of formula aryl-B(OH)₂ oralkyl-B(OH)₂.
 68. The method of claim 58, further comprising removingthe Alk group of the compound of formula XXIV to form a compound offormula XXV or a salt thereof, the compound of formula XXV having thestructure:

wherein Y, R⁴, n, m, R⁵, p, and R¹ have the definitions provided withrespect to the compounds of formula XXII, XXIII, and XXIV.
 69. Themethod of claim 68, wherein the compound of formula XXIV is reacted inthe presence of a hydroxide base to produce the compound of formula XXV.70. The method of claim 69, wherein the hydroxide base is selected fromLiOH, NaOH, KOH, or Ca(OH)₂.